11-Deoxy-2,2-difluoro-ω-aryl-PGE compounds

ABSTRACT

11-Deoxy prostaglandin type compounds, i.e. prostaglandin type compounds in which the 11-hydroxy group is replaced by hydrogen, are disclosed, with processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, and labor induction at term.

This is a division of application Ser. No. 609,410, filed Sept. 2, 1975.

BACKGROUND OF THE INVENTION

This invention relates to novel compositions of matter, to novel methodsfor producing those, and to novel chemical intermediates useful in thoseprocesses. Particularly, this invention relates to certain novel analogsof prostaglandin E and prostaglandins F.sub.α and F.sub.β, in which the11-hydroxy is replaced by hydrogen, i.e. the ring carbon atom adjacentto the site of attachment of the side chain attached at C-12 bears nohydroxyl substituent.

The known prostaglandins include, for example, prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂), prostaglandin F₁ alpha and beta (PGF₁α andPGF₁β) and prostaglandin F₂ alpha and beta (PGF₂α and PGF₂β). Each ofthe above-mentioned known prostaglandins is a derivative of prostanoicacid which has the following structure and atom numbering: ##STR1## See,for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), andreferences cited therein. A systematic name for prostanoic acid is7-[(2β-octyl)-cyclopent-1α-yl]-heptanoic acid.

PGE₁ has the following structure: ##STR2##

PGE₂ has the following structure: ##STR3##

PGF₁α has the following structure: ##STR4##

PGF₁β has the following structure: ##STR5##

PGF₂α has the following structure: ##STR6##

PGF₂β has the following structure: ##STR7##

In formulas II to VII, as well as in the formulas given hereinafter,broken line attachments to the cyclopentane ring indicate substituentsin alpha configuration, i.e., below the plane of the cyclopentane ring.Heavy solid line attachments to the cyclopentane ring indicatesubstituents in beta configuration, i.e., above the plane of thecyclopentane ring. The side-chain hydroxy at C-15 at formulas II to VIIis in S configuration. See Nature, 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins.

Molecules of the known prostaglandins each have several centers ofasymmetry, and can exist in racemic (optically inactive) form and ineither of the two enantiomeric (optically active) forms, i.e. thedextrorotatory and levorotatory forms. As drawn, formulas II to VII eachrepresent the particular optically active form of the prostaglandinwhich is obtained from certain mammalian tissues, for example, sheepvesicular glands, swine lung, or human seminal plasma, or by carbonyland/or double bond reduction of that prostaglandin. See, for example,Bergstom et Bergstrom cited above. The mirror image of each of formulasII to VII represents the other enantiomer of that prostaglandin. Theracemic form of a prostaglandin contains equal numbers of bothenantiomeric molecules, and one of formulas II to VII and the mirrorimage of that formula is needed to represent correctly the correspondingracemic prostaglandin. For convenience hereinafter, use of the termsPGE₁, PGE₂, PGF₁α, PGF₁β, PGF₂α, PGF₂β, and the like, will mean theoptically active form of that prostaglandin with the same absoluteconfiguration as PGE₁ obtained from mammalian tissues. When reference tothe racemic form of one of those prostaglandins is intended, the word"racemic" or "dl" will precede the prostaglandin name, thus, "racemicPGE₂ " or "dl-PGF₂α ".

PGE₁, PGE₂, PGF₁α, PGF₂α, PGF₁β, and PGF₂β and their esters, acylatesand pharmacologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bergstrom et al.,Pharmacol. Rev. 20, 1 (1968) and references cited therein. A few ofthose biological responses are systemic blood pressure lowering in thecase of the PGE and PGF.sub.β compounds as measured, for example, inanesthetized (pentobarbital sodium) pentolinium-treated rats withindwelling aortic and right heart cannulas; stimulation of smooth muscleas shown, for example, by tests on strips on guinea pig ileum, rabbitduodenum, or gerbil colon; potentiation of other smooth musclestimulants; lipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of the PGE compounds asshown in dogs with secretion stimulated by food or histamine infusion;activity on the central nervous system; controlling spasm andfacilitating breathing in asthmatic conditions; and decreasing bloodplatelet adhesiveness as shown by platelet-to-glass adhesiveness, andinhibition of blood platelet aggregation and thrombus formation inducedby various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbitsand monkeys.

For example, these compounds and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 μg. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE, PGF.sub.α and PGF.sub.β compounds are useful in the treatmentof asthma. For example, these compounds are useful as bronchodilators oras inhibitors of mediators, such as SRS-A, and histamine which arereleased from cells activated by an antigen-antibody complex. Thus,these compounds control spasm and facilitate breathing in conditionssuch as bronchial asthma, bronchitis, bronchiectasis, pneumonia andemphysema. For these purposes, these compounds are administered in avariety of dosage forms, e.g., orally in the form of tablets, capsules,or liquids; rectally in the form of suppositories; parenterally,subcutaneously, or intramuscularly, with intravenous administrationbeing preferred in emergency situations; by inhalation in the form ofaerosols or solutions for nebulizers; or by insufflation in the form ofpowder. Doses in the range of about 0.01 to 5 mg. per kg. of body weightare used 1 to 4 times a day, the exact dose depending on the age,weight, and condition of the patient and on the frequency and route ofadministration. For the above use these prostaglandins can be combinedadvantageously with other antiasthmatic agents, such as sympathomimetics(isoproterenol, phenylephrine, epinephrine, etc.); xanthine derivatives(theophylline and aminophylline); and corticosteroids (ACTH andprednisolone). Regarding use of these compounds see M. E. Rosenthale, etal., U.S. Pat. No. 3,644,638.

The PGE compounds are useful in mammals, including man and certainuseful animals, e.g., dogs and pigs, to reduce and control excessivegastric secretion, thereby reducing or avoiding gastrointestinal ulcerformation, and accelerating the healing of such ulcers already presentin the gastrointestinal tract. For this purpose, the compounds areinjected or infused intravenously, subcutaneously, or intramuscularly inan infusion dose range about 0.1 μg. to about 500 μg. per kg. of bodyweight per minute, or in a total daily dose by injection or infusion inthe range about 0.1 to about 20 mg. per kg. of body weight per day, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration.

The PGE, PGF.sub.α and PGF.sub.β compounds are useful whenever it isdesired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, and to remove or prevent the formation ofthrombi in mammals, including man, rabbits, and rats. For example, thesecompounds are useful in the treatment and prevention of myocardialinfarcts, to treat and prevent post-operative thrombosis, to promotepatency of vascular grafts following surgery, and to treat conditionssuch as atherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF.sub.α, and PGF.sub.β compounds are especially useful asadditives to blood, blood products, blood substitutes, and other fluidswhich are used in artificial extracorporeal circulation and perfusion ofisolated body portions, e.g., limbs and organs, whether attached to theoriginal body, detached and being preserved or prepared for transplant,or attached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE compound, for example, is useful in place of or incombination with less than usual amounts of these known smooth musclestimulators, for example, to relieve the symptoms of paralytic ileus, orto control or prevent atonic uterine bleeding after abortion ordelivery, to aid in expulsion of the placenta, and during thepuerperium. For the latter purpose, the PGE compound is administered byintravenous infusion immediately after abortion or delivery at a dose inthe range about 0.01 to about 50 μg. per kg. of body weight per minuteuntil the desired effect is obtained. Subsequent doses are given byintravenous, subcutaneous, or intramuscular injection or infusion duringpuerperium in the range 0.01 to 2 mg. per kg. of body weight per day,the exact dose depending on the age, weight, and condition of thepatient or animal.

The PGE and PGF.sub.β compounds are useful as hypotensive agents toreduce blood pressure in mammals, including man. For this purpose, thecompounds are administered by intravenous infusion at the rate about0.01 to about 50 μg. per kg. of body weight per minute or in single ormultiple doses of about 25 to 500 μg. per kg. of body weight total perday.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful in place ofoxytocin to induce labor in pregnant female animals, including man,cows, sheep, and pigs, at or near term, or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispurpose, the compound is infused intravenously at a dose of 0.01 to 50μg. per kg. of body weight per minute until or near the termination ofthe second stage of labor, i.e., expulsion of the fetus. These compoundsare especially useful when the female is one or more weeks post-matureand natural labor has not started, or 12 to 60 hours after the membraneshave ruptured and natural labor has not yet started. An alternativeroute of administration is oral.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful in controllingthe reproductive cycle in menstruating female mammals. By the termmenstruating female mammals is meant animals which are mature enough tomenstruate but not so old that regular menstruation has ceased. For thispurpose the prostaglandin is administered systemically at a dose levelin the range 0.01 mg. to about 20 mg. per kg. of body weight of thefemale mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Intravaginal and intrauterineroutes are alternate methods of administration. Additionally, expulsionof an embryo or a fetus is accomplished by similar administration of thecompound during the first or second trimester of the normal mammaliangestation period.

The PGE and PGF compounds are useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by PGE and PGF compounds isuseful in assisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus, cervical tears, or infections. It isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the PGE and PGF compounds areadministered locally or systemically.

PGE₂, for example, is administered orally or vaginally at doses of about5 to 50 mg. per treatment of an adult female human, with from one tofive treatments per 24 hour period. PGE₂ is also administeredintramuscularly or subcutaneously at doses of about one to 25 mg. pertreatment. The exact dosages for these purposes depend on the age,weight, and condition of the patient or animal.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in virto andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGE, PGF.sub.α, and PGF.sub.β compounds are also useful in reducingthe undesirable gastrointestinal effects resulting from systemicadministration of anti-inflammatory prostaglandin synthetase inhibitors,and are used for that purpose by concomitant administration of theprostaglandin and the anti-inflammatory prostaglandin synthetaseinhibitor. See Partridge et al., U.S. Pat. No. 3,781,429, for adisclosure that the ulcerogenic effect induced by certain non-steroidalanti-inflammatory agents in rats in inhibited by concomitant oraladministration of certain prostaglandins of the E and A series,including PGE₁, PGE₂, PGE₃, 13,14-dihydro-PGE₁, and the corresponding11-deoxy-PGE compounds. The prostaglandins are useful, for example, inreducing the undesirable gastrointestinal effects resulting fromsystemic administration of indomethacin, phenylbutazone, and aspirin.These are substances specifically mentioned in Partridge et al. asnon-steroidal anti-inflammatory agents. But these are also known to beprostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, for example, indomethacin,aspirin, or phenylbutazone is administered in any of the ways known inthe art to alleviate an inflammatory condition, for example, in anydosage regimen and by any of the known routes of systemicadministration.

The prostaglandin is administered along with the anti-inflammatoryprostaglandin synthetase inhibitor either by the same route ofadministration or by a different route. For example, if theanti-inflammatory substance is being administered orally, theprostaglandin is also administered orally or, alternatively, isadministered rectally in the form of a suppository or, in the case ofwomen, vaginally in the form of a suppository or a vaginal device forslow release, for example as described in U.S. Pat. No. 3,545,439.Alternatively, if the anti-inflammatory substance is being administeredrectally, the prostaglandin is also administered rectally, or,alternatively, orally or, in the case of women vaginally. It isespecially convenient when the administration route is to be the samefor both anti-inflammatory substance and prostaglandin, to combine bothinto a single dosage form.

The dosage regimen for the prostaglandin in accord with this treatmentwill depend upon a variety of factors, including the type, age, weight,sex and medical condition of the mammal, the nature and dosage regimenof the anti-inflammatory synthetase inhibitor being administered to themammal, the sensitivity of the particular individual mammal to theparticular synthetase inhibitor with regard to gastrointestinal effects,and the particular prostaglandin to be administered. For example, notevery human in need of an anti-inflammatory substance experiences thesame adverse gastrointestinal effects when taking the substance. Thegastrointestinal effects will frequently vary substantially in kind anddegree. But it is within the skill of the attending physician orveterinarian to determine that administration of the anti-inflammatorysubstance is causing undesirable gastrointestinal effects in the humanor animal subject and to prescribe an effective amount of theprostaglandin to reduce and then substantially to eliminate thoseundesirable effects.

The PGF.sub.α compounds are useful in the treatment of shock(hemorrhagic shock, endotoxin shock, cardiogenic shock, surgical shock,or toxic shock). Shock is marked by pallor and clamminess of the skin,decreased blood pressure, feeble and rapid pulse, decreased respiration,restlessness, anxiety, and sometimes unconsciousness. Shock usuallyfollows cases of injury and trauma. Expert and fast emergency measuresare required to successfully manage such shock conditions. Accordingly,prostaglandins, combined with a pharmaceutical carrier which adapts theprostaglandin for intramuscular, intravenous, or subcutaneous use, areuseful, especially in the early stages of shock where increased bloodpressure is a critical factor, for aiding and maintaining adequate bloodflow, perfusing the vital organs, and exerting a presser response byconstricting veins and raising blood pressure to normal levels.Accordingly, the prostaglandins are useful in preventing irreversibleshock which is characterized by a profound fall in blood pressure,dilation of veins, and venus blood pooling. In the treatment of shock,the prostaglandin is infused at a dose of 0.1 - 25 mcg./kg./min. Theprostaglandin may advantageously be combined with knownvasoconstrictors; such as phenoxybenzamine, norepinephrine, norephrine,and the like. Further, when used in the treatment of shock theprostaglandin may be combined with steroids (such as, hydrocortisone ormethylprednisolone), tranquilizers, and antibiotics (such as lincomycinor clindamycin).

The PGE, PGF.sub.α, and PGF.sub.β are useful in domestic animals as anabortifacient (especially for feedlot heifers), as an aid to estrusdetection, and for regulation or synchronization of estrus. Domesticanimals include horses, cattle, sheep and swine.

The regulation or synchronization of estrus, as well as estrusdetection, allows for more efficient management of both conception andlabor by enabling a herdsman to breed all his female animals in shortpredefined intervals. This results in a higher percentage of live birthsthan the percentage achieved by natural control. The prostaglandin isinjected or applied in a feed at doses of 0.1-100 mg. per animal per dayand may be combined with other agents such as steroids. Dosing scheduleswill depend on the species treated. For example, mares are givenprostaglandin 5-8 days after ovulation and return to estrus. Cattle, aretreated at regular intervals over a 3 week period to advantageouslybring all into estrus at the same time.

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel11-deoxy-prostaglandin analogs. It is a further purpose to provideesters, lower alkanoates, and pharmacologically acceptable salts of saidanalogs. It is a further purpose to provide novel processes forpreparing said analogs and esters. It is still a further purpose toprovide novel intermediates useful in said processes.

The presently described acids and esters of the 11-deoxy-prostaglandinanalogs include compounds of the following formula, and also the racemiccompounds of that formula and the mirror image thereof: ##STR8##

In Formula VIII, R₁ is hydrogen, alkyl of one to 12 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2,or 3 chloro, or alkyl of one to 3 carbon atoms, inclusive, or apharmacologically acceptable cation. R₂ is fluoro or hydrogen. Thesymbol "m" is an integer 1, 2 or 3. X is --(CH₂)₃ --, cis --CH═CH--CH₂--, or cis --CH₂ --CH═CH--. E is ##STR9## Y is --CH₂ CH₂ -- or trans--CH═CH--. M is ##STR10## wherein R₅ and R₆ are hydrogen or methyl, withthe proviso that R₅ is methyl only when R₆ is hydrogen, and R₆ is methylonly when R₅ is hydrogen. L is ##STR11## or a mixture of ##STR12##wherein R₃ and R₄, which can be the same or different, are hydrogen,methyl, or fluoro, with the proviso that one of R₃ and R₄ is fluoro onlywhen the other is hydrogen or fluoro. R₇ is (1) --(CH₂)_(n) --CH₃,wherein n is one to 5, inclusive, ##STR13## wherein T is alkyl of 1 to 3carbon atoms, inclusive, chloro, fluoro, trifluoromethyl, or --OR₈,wherein R₈ is alkyl of 1 to 3 carbon atoms, inclusive, and s is zero to3, inclusive, the various T's being the same or different, and no morethan two T's are other than alkyl, ##STR14## wherein T and s are asdefined above, with the proviso that R₇ is --(CH₂)_(n) --CH₃, wherein nis as defined above, only when at least one of R₂, R₃, or R₄ is fluoro,with the further proviso that R₇ is ##STR15## wherein T and s are asdefined above, only when at least one of R₂, R₃ and R₄ is fluoro or X is--CH₂ --CH═CH--, and with the further proviso that R₇ is ##STR16##wherein T and s are as defined above, only when R₃ and R₄ are hydrogenor methyl, being the same or different.

Formula VIII includes the separate isomers wherein M is either ##STR17##i.e. where --OR₆ is in either natural (alpha or L) or epi (beta or D)configuration, wherein D and L relate to the absolute configuration ofD- or L-glyceraldehyde using the standard Fischer convention. See M.Hamberg, Advan. Biosci., 9, 847 (1973). Referring to the prostanoic acidatom numbering (Formula I above), the point of attachment corresponds toC-15, and, herein regardless of the variation in the C-1 to C-7 carbonchain, these epimers are referred to as C-15 epimers.

Formula VIII represents 11-deoxy-prostaglandin E₂ -,11-deoxy-4,5-cis-didehydro prostaglandin E₁ -, 11-deoxy-prostaglandinF.sub.α - and 11-deoxy-prostaglandin F.sub. β -type compounds, i.e.analogs of prostaglandin E₂, 4,5-cis-didehydroprostaglandin E₁,prostaglandin F.sub.α and prostaglandin F.sub.β in which the 11-hydroxyis replaced by hydrogen. For example, Formula VIII represents11-deoxy-2,2-difluoro-15-methyl-PGE₂ when R₁ is hydrogen, R₂ is fluoro,"m" is one, X is cis--CH═CH--CH₂ --, E is ##STR18## Y is trans--CH═CH--, M is ##STR19## L is ##STR20## and R₇ is --(CH₂)₃ CH₃. FormulaVIII represents 11-deoxy-16,16-difluoro-PGE₂, methyl ester, when R₁ ismethyl, R₂ is hydrogen, "m" is one, X is cis--CH═CH--CH₂, E is ##STR21##Y is trans --CH═CH--, M is ##STR22## L is ##STR23## and R₇ is --(CH₂)₃CH₃. Formula VIII represents 11-deoxy-4,5-cis-didehydro-17phenyl-18,19,20-trinor-PGE₁ when R₁ is hydrogen, R₂ is hydrogen, "m" isone, X is cis-CH₂ --CH═CH--, E is ##STR24## Y is trans-CH═CH--, M is##STR25## L is ##STR26## and R₇ is benzyl. Formula VIII represents11-deoxy-2,2-difluoro-17-(p-fluorophenyl)-18,19,20-trinor-PGE₂, methylester, when R₁ is methyl, R₂ is fluoro, "m" is one, X is cis-CH═CH--CH₂--, E is ##STR27## Y is trans-CH═CH--, M is ##STR28## L is ##STR29## andR₇ is p-fluorobenzyl. Formula VIII represents11-deoxy-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-PGE₂ when R₁ ishydrogen, R₂ is fluoro, "m" is one, X is cis-CH═CH--CH₂ --, E is##STR30## Y is trans-CH═CH--, M is ##STR31## L is ##STR32## and R₇ isphenoxy.

Formula VIII represents11-deoxy-4,5-cis-didehydro-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₁,methyl ester, when R₁ is methyl, R₂ is hydrogen, "m" is one, X iscis-CH₂ --CH═CH--, E is ##STR33## Y is trans-CH═CH--, M is ##STR34## Lis ##STR35## and R₇ is m-(trifluoromethyl)phenoxy.

An alternate name for 11-deoxy-PGE₂ is 10,11-dihydro-PGA₂. Thesecompounds may also be named as prostanoic acid derivatives. For example,11-deoxy-PGE₂ is (5Z, 13E, 15S)-15-hydroxy-9-oxoprosta-5,13-dienoicacid.

As in the case of Formulas II to VII, Formula VIII wherein M is##STR36## i.e. wherein the C-15 hydroxyl or ether group is attached tothe side chain in alpha configuration are each intended to representoptically active prostanoic acid derivatives with the same absoluteconfiguration as PGE₁ obtained from mammalian tissues.

Also included within this invention are the 15-epimer compounds ofFormula VIII wherein M is ##STR37## These are identified hereinafter as"15-epi" compounds by the appropriate prefix in the name. For example,"11-deoxy-15-epi-16,16-difluoro-PGE₂, methyl ester", identifies the15-epimeric compound corresponding to the Formula VIII example aboveexcept that it has the beta configuration at C-15 instead of the naturalalpha configuration of 11-deoxy-PGE₁.

The Formula VIII plus its mirror image describes a racemic compoundwithin the scope of this invention. For convenience hereinafter, such aracemic compound is designated by the prefix "racemic" ("rac" or "dl")before its name; when that prefix is absent, the intent is to designatean optically active compound represented by the Formula VIII.

With regard to R₁ of Formula VIII, examples of alkyl of one to 12 carbonatoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and isomeric formsthereof. Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive,which includes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cycloocytyl, cyclononyl, and cyclodecyl. Examples ofaralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl,1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl,2-(1-naphthylethyl), and 1-(2-naphthylmethyl). Examples of phenylsubstituted by one to 3 chloro or alkyl of one to 4 carbon atoms,inclusive, are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

The novel 11-deoxy PG analogs of this invention correspond to theprostaglandins described above, in that the novel PG analogs exhibitprostaglandin-like activity. Specifically, the 11-deoxy-PGE-,PGF.sub.α - and PGF.sub.β -type compounds of this invention respectivelycorrespond to the PGE, PGF.sub.α and PGF.sub.β compounds describedabove, in that these novel PGE-, PGF.sub.α - and PGF.sub.β -typecompounds are useful for each of the above described purposes for whichthe PGE, PGF.sub.α and PGF.sub.β compounds are used, and arerespectively used in the same manner as the PGE, PGF.sub.α and PGF.sub.βcompounds, as described above.

The prostaglandins described above are all potent in causing multiplebiological responses even at low doses. Moreover, for many applicationsthese prostaglandins have an inconveniently short duration of biologicalactivity. In striking contrast, the novel prostaglandin analogs of thisinvention are substantially more selective with regard to potency incausing prostaglandin-type responses, and have a substantially longerduration of biological activity.

Accordingly, each of the novel prostaglandin analogs of this inventionis surprisingly and unexpectedly more useful than one of thecorresponding prostaglandins, described above, for at least one of thepharmacological purposes indicated for the corresponding prostaglandin,because each of the novel prostaglandin analogs has a different andnarrower spectrum of biological potency than the correspondingprostaglandin, and therefore is more specific in its activity and causessimilar and fewer undesired side effects than when the correspondingprostaglandin is used for the same purpose. Moreover, because of itsprolonged activity, fewer and smaller doses of the novel prostaglandinanalog are frequently used to obtain the desired result.

Because of their unique chemical structure, the novel prostaglandinanalogs of this invention are less sensitive to dehydration orrearrangement than the PGE-type prostaglandins and enjoy increasedchemical stability and longer shelf life.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope ofFormula VIII are preferred. With reference to the definitions givenabove, it is preferred that "m" be the integers one or 3. It isespecially preferred that "m" be one. It is further preferred that M be##STR38## When R₇ is --(CH₂)_(n) --CH₃, it is preferred that "n" be 3.When R₇ is ##STR39## it is preferred that "s" be zero or one and T befluoro, chloro or trifluoromethyl, especially m- or p-fluoro, m- orp-chloro and m- or p-trifluoromethyl. When one of R₅ or R₆ is methyl, itis preferred that both R₃ and R₄ be hydrogen. When one or both of R₃ andR₄ are methyl or fluoro, it is preferred that both of R₅ and R₆ behydrogen. When R₇ is --(CH₂)_(n) --CH₃, it is preferred that at leastone of R₃, R₄, R₅ annd R₆ be other than hydrogen. When E is thosecompounds wherein E is ##STR40## are preferred.

Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally, sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins. These qualities are advantageous because they facilitatemaintaining uniform levels of these compounds in the body with fewer,shorter, or smaller doses, and make possible self-administration by thepatient.

The 11-deoxy-prostaglandin analogs encompassed by Formula VIII,including their alkanoates, are used for the purposes described above inthe free acid form, in ester form, or in pharmacologically acceptablesalt form. When the ester form is used, the ester is any of those withinthe above definition of R₁. However, it is preferred that the ester bealkyl of one to 12 carbon atoms, inclusive. Of those alkyl, methyl andethyl are especially preferred for optimum absorption of the compound bythe body or experimetal animal system; and straight-chain octyl, nonyl,decyl, undecyl, and dodecyl are especially preferred for prolongedactivity in the body or experimental animal.

Pharmacologically acceptable salts of these Formula VIII compoundsuseful for the purposes described above are those with pharmacologicallyacceptable metal cations, ammonium, amine cations, or quaternaryammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methyl-hexylamine, declyamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, 1-adamantanamine and likealiphatic, cycloaliphatic, and araliphatic amines containing up to andincluding about 18 carbon atoms, as well as heterocyclic amines, e.g.,piperidine, morpholine, pyrrolidine, piperazine, and lower-alkylderivatives thereof, e.g., 1-methylpiperidine, 4-ethylmorpholine,1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine,2-methylpiperidine, and the like, as well as amines containingwater-solubilizing or hydrophilic groups, e.g., mono-, di-, andtriethanolamine, ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, glactamine,N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like. Salts yielding crystalline PG-typecompounds such as 1-adamantanamine salts, are preferred.

Examples of suitable pharmocologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The compounds encompassed by Formula VIII are used for the purposesdescribed above in free hydroxy form or also in the form wherein thehydroxy moieties are transformed to lower alkanoate moieties, e.g., --OHto --OCOCH₃. Examples of lower alkanoate moieties are acetoxy,propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy,octanoyloxy, and branched chain alkanoyloxy isomers of those moieties.Especially preferred among these alkanoates for the above describedpurposes are the acetoxy compounds. These free hydroxy and alkanoyloxycompounds are used as free acids, as esters, and in salt form all asdescribed above.

As discussed above, the compounds of Formula VIII are administered invarious ways for various purposes; e.g., intravenously, intramuscularly,subcutaneously, orally, intravaginally, rectally, buccally,sublingually, topically, and in the form of sterile implants forprolonged action. For intravenous injection or infusion, sterile aqueousisotonic solutions are preferred. For that purpose, it is preferredbecause of increased water solubility that R₁ in the Formula VIIIcompound be hydrogen or a pharmacologically acceptable cation. Forsubcutaneous or intramuscular injection, sterile solutions orsuspensions of the acid, salt, or ester form in aqueous or non-aqueousmedia are used. Tablets, capsules, and liquid preparations such assyrups, elixirs, and simple solutions, with the usual pharmaceuticalcarriers, are used for oral sublingual administration. For rectal orvaginal administration suppositories prepared as known in the art areused. For tissue implants, a sterile tablet or silicone rubber capsuleor other object containing or impregnated with the substance is used.

A number of 11-deoxy prostaglandin compounds are reported in theliterature. P. Crabbe and A. Guzman, Tetrahedron Lett. No. 2, 115, 1972,have reported the synthesis of dl-11-deoxy-PGE₂. dl-11-Deoxy-PGF₂α isalso described in the same publication. Belgian Pat. No. 766 521(Derwent No. 72021S) issued to Roussel-Uclaf claims15α-hydroxy-9-oxo-5-cis-13-trans-prostadienoic acid (11-deoxy-PGE₂), itsmethyl ester, and its sodium salt. That patent also claims compounds ofthe general formula ##STR41## in which R represents hydrogen or loweralkyl, n is 2, 3, or 4, and m is 3, 4, or 5, including certain salts.See also Belgium Pat. No. 784 809 (Derwent No. 81307T), Netherlands Pat.Nos. 73 01094 (Derwent No. 46023U), 73 05303 (Derwent No. 66606U) and 7208955 (Derwent No. 03130U).

The 11-deoxy prostaglandin analogs encompassed by Formula VIII areproduced by the reactions and procedures described and exemplifiedhereinafter.

Reference to Chart A herein will make clear the process steps startingin Chart A with the aldehyde of Formula IX to provide PGE₂ compound ofFormula XVI. The aldehyde of Formula IX is known in the art. See Crabbeet al., Tetrahedron Letters, No. 2, 115 (1972). This procedure is doneby steps known in the art. See E. J. Corey et al., J. Am. Chem. Soc. 91,5675 (1969). ##STR42##

In Chart A, "m", R₂, L and R₇ are as defined above; M₁ is either##STR43## and M₂ is ##STR44## wherein R₉ is a "blocking group" which isdefined as any group which replaces hydrogen of the hydroxyl groups,which is not attacked by nor is reactive to the reagents used in therespective transformations to the extent that the hydroxyl group is, andwhich is subsequently replaceable by hydrogen at a later stage in thepreparation of the prostaglandin-like products. Several blocking groupsare known in the art, e.g. tetrahydropyranyl and substitutedtetrahydropyranyl (see Corey, Proceedings of the Robert A. WelchFoundation Conferences on Chemical Research, XII, Organic Synthesis, pp.55-79 (1969)). Those blocking groups which have been found usefulinclude (a) tetrahydropyranyl; (b) tetrahydrofuranyl; or (c) a group ofthe formula ##STR45## wherein R₁₀ is alkyl of one to 18 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one,2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₁₁ and R₁₂are the same or different, being hydrogen, alkyl of one to 4 carbonatoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkylof one to 4 carbon atoms, inclusive, or, when R₁₁ and R₁₂ are takentogether, --(CH₂)_(b) -- or --(CH₂)_(c) --O--(CH₂)_(d) -- wherein b is3, 4, or 5, c is one, 2, or 3, and d is one, 2, or 3 with the provisothat c plus d is 2, 3, or 4, and wherein R₁₃ is hydrogen or phenyl.

The Formula X compound is obtained by Wittig alkylation of IX, using thesodio derivative of an appropriate 2-oxophosphonate having the formula##STR46## wherein R₁₄ is alkyl of one to 8 carbon atoms, especiallymethyl. The trans enone lactone is obtained stereospecifically (see D.H. Wadsworth et al., J. Org. Chem. Vol. 30, p. 680 (1965)).

The phosphonates are prepared and used by methods known in the art. SeeWadsworth et al., reference cited above. Conveniently, the appropriatealiphatic acid ester is condensed with dimethyl methylphosphonate in thepresence of n-butyllithium. For this purpose, acids of the generalformula ##STR47## are used in the form of the lower alkyl ester,preferably methyl or ethyl esters. For this purpose methyl esters arereadily formed from the acid by reaction with diazomethane. These acidsare known in the art or can be prepared by methods known in the art.

Alternatively, there can be employed in the reaction, certainphosphoranes of the formula ##STR48## These phosphoranes are preparedand used by methods known in the art. Conveniently, the appropriateketone compound of the formula ##STR49## wherein Hal is chloro, bromo oriodo, is condensed with triphenylphosphine and the condensation productis treated with alkali to produce the desired phosphorane compound. Thehaloketone starting compound is prepared in a known way.

The formula XI compound is obtained as a mixture of alpha and betahydroxy isomers by reduction of X. For this reduction, use is made ofany of the known ketonic carbonyl reducing agents which do not reduceester or acid groups or carbon-carbon double bonds when the latter isundesirable. Examples of those are the metal borohydrides, especiallysodium, potassium, and zinc borohydrides, lithium (tri-tert-butoxy)aluminum hydride, metal trialkoxy borohydrides, e.g., sodiumtrimethoxyborohydride, lithium borohydride, and in those situations inwhich carbon-carbon double bond reduction is not a problem, the boranes,e.g., disiamylborane (bis-3-methyl-2-butylborane).

For production of natural-configuration prostaglandins, the alpha formof the Formula XI compounds is separated from the beta isomer by silicagel chromotography using methods known in the art.

The Formula XII lactone is obtained by replacing the hydrogen atoms ofthe hydroxyl groups of XI with a blocking group. When the blocking groupis tetrahydropyranyl or tetrahydrofuranyl, the appropriate reagent, e.g.2,3-dihydropyran or 2,3-dihydrofuran, is used in an inert solvent suchas dichloromethane, in the presence of an acid condensing agent such asp-toluenesulfonic acid or pyridine hydrochloride. The reagent is used inlarge excess, preferably 1.2 to 20 times theory. The reaction is carriedout at about 20-50° C.

When the blocking group is of the formula ##STR50## as defined above,the appropriate reagent is a vinyl ether, e.g. isobutyl vinyl ether orany vinyl ether of the formula

    R.sub.10 --O--C(R.sub.11)═CR.sub.12 R.sub.13

wherein R₁₀, R₁₁, R₁₂, and R₁₃ are as defined above; or an unsaturatedcyclic or heterocyclic compound, e.g. 1-cyclohexen-1-yl methyl ether##STR51## or 5,6-dihydro-4-methoxy-2H-pyran ##STR52## See C. B. Reese etal., J. Am. Chem. Soc. 89, 3366 (1967). The reaction conditions for suchvinyl ethers and unsaturates are similar to those for dihydropyranabove.

The Formula XIII lactol is obtained on reduction of lactone XII withoutreducing the ethylenic group. For this purpose, diisobutylaluminumhydride is used as known in the art. The reduction is preferably done at-60 to -78° C.

The stereochemistry at the C-15 position is preserved in transforming XIto XII to XIII. For example, a 15β-epimer compound XI yields a15β-epimer compound XIII.

The Formula XIV compound is obtained from the Formula XIII lactol by theWittig reaction, using a Wittig reagent derived from the appropriateω-carboxyalkyltriphenylphosphonium bromide, HOOC--(R₂)₂ C--(CH₂)_(m)--CH₂ --P(C₆ H₅)₃ Br, and sodio dimethylsulfinylcarbanide. Thephosphonium compounds are known in the art or are readily available,e.g. by reaction of an ω-bromoaliphatic acid with triphenylphosphine.

When R₂ is fluoro, the corresponding ω-bromoaliphatic acid used toprepare the phosphonium compound can be prepared, for example, byreducing methyl furoate to methyltetrahydrofuroate by hydrogenationusing a 5 percent palladium on charcoal catalyst. Themethyltetrahydrofuroate is converted tomethyl-2-acetoxy-5-bromo-pentanoate by reaction with HBr and aceticanhydride, under anhydrous conditions. Themethyl-2-acetoxy-5-bromo-pentanoate is transformed to the correspondingalcohol methyl-2-hydroxy-5-bromo-pentanoate by treatment with ice coldmethanol saturated with HBr and then the alcohol is transformed to thecorresponding ketone methyl-2-oxo-5-bromo-pentanoate by reaction withJones reagent. The ketone is transformed tomethyl-2,2-difluoro-5-bromo-pentanoate by reaction with molybdenumhexafluoride in boron trifluoride (Fluoreze M by PCR Incorporated) at-35° to 45° C and that methyl ester is hydrolyzed in aqueous HBr toyield 2,2-difluoro-5-bromo-pentanoic acid.

The Formula XIV compound can be converted to the corresponding FormulaXV compound by the Jones regent or Collins reagent, which is in turnconverted to the PGE₂ compound XVI by mild acid hydrolysis.

The Formula XIV compound can be converted to the PGF₂ compound XVII byremoval of the blocking group R₉ by mild acid hydrolysis, for exampleusing acetic acid.

Referring to Chart B, there is shown the transformation of lactone XI to15-methyl ether-PGE₂ -type products of Formula XX. In chart B, "m", M₁,R₂, L, and R₇ have the same meanings as above. M₃ is either ##STR53##The starting materials are available from the steps of Chart A above orare readily available by methods known in the art.

The Formula XVIII compound is prepared by alkylation of the side-chainhydroxy of the Formula XI compound thereby replacing hydroxy with the--OCH₃ moiety. For this purpose, diazomethane may be employed,preferably in the presence of a Lewis acid, e.g. boron trifluorideetherate, aluminum chloride, or fluoboric acid. See Fieser et al.,"Reagents for Organic Synthesis", John Wiley and Sons, Inc. N.Y. (1967),p. 191. The reaction is carried out of mixing a solution of thediazoalkane in a suitable inert solvent, preferably diethyl ether, withthe Formula XI compound. Generally the reaction proceeds at about 25° C.

Another method for the alkylation of the side chain hydroxy is byreaction with an alcohol in the presence of boron trifluoride etherate.Thus, methanol and boron trifluoride etherate yield the methyl ether.The reaction is done at about 25° C. and is conveniently followed withthin layer chromotography (TLC).

Another method for the alkylation of the side-chain hydroxy is by thereaction of an alkyl halide, e.g. methyl iodide, in the presence of ametal oxide or hydroxide, e.g. barium oxide, silver oxide, or bariumhydroxide. An inert solvent may be beneficial, for example benzene ordimethylformamide. The reactants are preferably stirred together andmaintained at temperatures of 25-75° C.

Still another method is by first converting the hydroxy to mesyloxy(i.e. methanesulfonate) or tosyloxy (i.e. toluenesulfonate) and thencetransforming the mesyloxy or tosyloxy to the --OCH₃ moiety by reactionwith a metal alkoxide, in an excess of methanol. The mesylate ortosylate is prepared by reaction of the Formula XI intermediate witheither methanesulfonyl chloride or toluenesulfonyl chloride in pyridine.Thereafter, the mesylate or tosylate is mixed with the appropriatepotassium or sodium methoxide or methanol in pyridine, the reactionproceeding smoothly at about 25° C. An equivalent amount of themethoxide based on the mesylate is preferred to avoid side reactions.This method, however, results in some isomerization at C-15, as well aspoor yield in many cases.

The Formula XIX compound is then obtained in the conventional manner,for example by low temperature reduction with diisobutylaluminum hydrideas discussed above for Chart A. The final 15-methyl ether-PGE₂ productXX is obtained from XIX by the same reactions and conditions discussedabove for the steps of Chart A.

Referring to Chart C, there is shown the transformation of lactone X tolactol XXIII useful for preparing 15-methyl-PG-type products. In ChartC, M₄ is ether ##STR54## M₅ is either ##STR55## wherein R₉ is as definedabove.

For the starting material X refer to Chart A and the discussionpertaining thereto. Intermediate XXI is obtained by replacing theside-chain oxo with M₄ by a conventional Grignard reaction, employingCH₃ MgHal. Next the hydrogen atom of the hydroxyl group is replaced withblocking group R₉ following the procedures of Chart A. Finally lactolXXIII is obtained by reduction of lactone XXII in the same mannerdiscussed above for Chart A. ##STR56##

The 15-alkyl-PGE and PGF-type products of this invention are obtainedfrom lactone XXII either with or without isolating the Formula XXIIIlactol, following the procedures discussed above for Chart A. The15-alpha and 15-beta isomers are separated by conventional means, forexample silica gel chromotography of the corresponding methyl esters atthe final product stages.

Referring to Chart D, there is shown the transformation of lactol XIIIto 4,5-didehydro-PGF₁.sub.α and 4,5-didehydro-PGE₁ -type compounds. InChart D, "m", R₂, M₁, M₂ and R₇ have the same meanings as above. L₁ is##STR57## M₆ is either ##STR58## A is alkyl of one to 4 carbon atoms,inclusive, phenyl, phenyl substituted with one or 2 fluoro, chloro, oralkyl of one to 4 carbon atoms, inclusive, or aralkyl of 7 to 12 carbonatoms, inclusive. R₁₅ is alkyl of 4 to 18 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkylof one to 4 carbon atoms, inclusive. R₁₆ is R₁ as defined above or silylof the formula --Si--(A)₃ wherein A is as defined above. The various A'sof a --Si--(A)₃ moiety are alike or different. For example, a --Si--(A)₃can be trimethylsilyl, dimethylpropylsilyl, dimethylphenylsilyl, ormethylphenylbenzylsilyl. Examples of alkyl of one to 4 carbon atoms,inclusive, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, and tert-butyl. ##STR59## Examples of aralkyl of 7 to 12carbon atoms, inclusive, are benzyl, phenethyl, α-phenylethyl,3-phenylpropyl, α-naphthylmethyl, and 2-(β-naphthyl)ethyl. Examples ofphenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4carbon atoms, inclusive, are p-chlorophenyl, m-fluorophenyl, o-tolyl,2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

The Formula XIII lactol is condensed to form the Formula XXIV enolethers. For this purpose, an alkoxymethylenetriphenylphosphorane isuseful. See, for example, Levine, J. Am. Chem. Soc. 80, 6150 (1958). Thereagent is conveniently prepared from a corresponding quaternaryphosphonium halide and a base, e.g., butyl lithium or phenyl lithium, ata low temperature, e.g. preferably below -10° C. The Formula XIII lactolis mixed with the reagent and the condensation proceeds smoothly withinthe temperature range -30° C. to +30° C. At higher temperatures theragent is unstable, whereas at low temperatures the rate of condensationis undesirably slow. Examples of thealkoxymethylenetriphenylphosphoranes preferred for forming the FormulaXXIV enol ethers are methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-,isobutoxy-, sec-butoxy-, and tert-butoxymethylenetriphenylphosphorane.

Various hydrocarbyloxymethylenetriphenylphosphoranes which can besubstituted for the alkoxymethylenetriphenylphosphoranes and aretherefore useful for preparing Formula XXIV intermediates wherein R₁₅ ishydrocarbyl, including alkoxy (of 4 to 18 carbon atoms)-, aralkoxy-,cycloalkoxy-, and aryloxymethylenetriphenylphosphoranes. Examples ofthese hydrocarbyloxymethylenetriphenylphosphoranes are 2-methylbutoxy-,isopentyloxy-, heptyloxy-, octyloxy-, nonyloxy-, tridecyloxy-,octadecykloxy, benzyloxy-, phenethyloxy-, p-methylphenethyloxy-,1-methyl-3-phenylpropyoxy-, cyclohexyloxy-, phenoxy-, andp-methylphenoxy-methylenetriphenyphosphorane. See, for example, OrganicReactions, Vol. 14, pages 346-348, John Wiley and Sons, Inc., N.Y.,(1965).

The Formula XXIV enol ether is hydrolyzed to the Formula XXV lactol.This hydrolysis is done under acidic conditions, for example withperchloric acid or acetic acid. Tetrahydrofuran is a suitable diluentfor this reaction mixture. Reaction temperatures of from 10° C. to 100°C. may be employed. The length of time required for hydrolysis isdetermined in part by the hydrolysis temperature. With aceticacid-water-tetrahydrofuran at about 60° C., several hours aresufficient.

The Formula XXV lactol is transformed to the Formula XXVI PGF-typeproducts by condensation with a Wittig reagent derived from3-carboxypropyltriphenylphosphonium halide and sodiomethylsulfinylcarbanide. Dimethylsulfoxide is conveniently used as asolvent, and the reaction may be done at about 25° C.

The various Formula XXIV and XXV intermediates are useful directly asproduced or they may be subjected to purification procedures, forexample silica gel chromatography or recrystallization.

The Formula XXVI PGF-type compound can be transformed to thecorresponding PGE-type compound of Formula XXIX. For this purpose theFormula XXVI compound is selectively silylated at the C-15 position, bychoice of reagents and conditions. Silylating agents are known in theart. See, for example, Pierce, "Silylation of Organic Compounds," PierceChemical Co., Rockford, Ill. (1968). Silylating agents of the type (A)₃SiN(G)₂, i.e. substituted silylamines wherein A is as defined above andG has the same definition as A, being the same or different, are usefulfor the above purpose at temperatures below about -25° C. A preferredtemperature range is about -35° to -50°. At higher temperatures somesilylation of C-9 hydroxyl groups as well as the C-15 hydroxyl groupoccurs, whereas at lower temperatures the rate of silylation isundesirably slow. Examples of silylamine type silylating agents suitablefor forming the Formula XXVII intermediates includepentamethylsilylamine, pentaethylsilylamine,N-trimethylsilyldiethylamine, 1,1,1-triethyl-N,N-dimethylsilylamine,N,N-diisopropyl-1,1,1-trimethylsilylamine,1,1,1-tributyl-N,N-dimethylsilylamine,N,N-dibutyl-1,1,1-trimethylsilylamine,1-isobutyl-N,N,1,1-tetramethylsilylamine,N-benzyl-N-ethyl-1,1,1-trimethylsilylamine,N,N,1,1-tetramethyl-1-phenylsilylamine,N,N-diethyl-1,1-dimethyl-1-phenylsilylamine,N,N-diethyl-1-methyl-1,1-diphenylsilylamine,N,N-dibutyl-1,1,1-triphenylsilylamine, and1-methyl-N,N,1,1-tetraphenylsilylamine. The reaction is carried out withexclusion of atmospheric moisture, for example, under a nitrogenatmosphere. It is conveniently done in a solvent such as acetone ordichloromethane, although the silylating agent itself, when used inexcess, may also serve as a liquid medium for the reaction. The reactionordinarily is completed in a few hours, and should be terminated whenthe C-15 hydroxyl group is silylated, to avoid side reactions. Theprogress of the reaction is conveniently monitored by thin-layerchromatography (TLC), utilizing methods known in the art.

An excess of the reagent over that stoichiometrically required is used,preferably at least a four-fold excess. The -COOH moiety may bepartially or even completely transformed to --COO--Si--(A)₃, additionalsilylating agent being used for this purpose. Whether or not this occursis immaterial for the success of the process, since --COOH groups arenot changed by the subsequent steps and --COO--Si(A)₃ groups are easilyhydrolyzed to --COOH groups.

The Formula XXVII silyl ether intermediate is oxidized to the FormulaXXVIII compound. Oxidation reagents useful for this transformation areknown in the art. An especially useful reagent for this purpose is theCollins reagent, i.e. chromium trioxide in pyridine. See J. C. Collinset al., Tetrahedron Lett., 3363 (1968). Dichloromethane is a suitablediluent for this purpose. A 6-8 fold excess of the oxidant beyond theamount necessary to oxidize the C-9 secondary hydroxy group of theFormula XXVII intermediate is used. Reaction temperatures of below 20°C. should be used. Preferred reaction temperatures are in the range -10°to +10° C. The oxidation proceeds rapidly and is usually complete inabout 5 to 20 minutes. Finally all silyl groups of the Formula XXVIIIintermediate are removed by hydrolysis, thereby forming the Formula XXIXPGE-type products. This hydrolysis is carried out by prior artprocedures known to be useful for transforming silyl ethers and silylesters to alcohols and carboxylic acids, respectively. See, for example,Pierce, cited above, especially p. 447 thereof. A mixture of water andsufficient of a water-miscible organic diluent to give a homogeneoushydrolysis reaction mixture represents a suitable reaction medium.Addition of a catalytic amount of an organic or inorganic acid hastensthe hydrolysis. The length of time required for the hydrolysis isdetermined in part by the hydrolysis temperature. With a mixture ofwater and methanol at 25° C., several hours is usually sufficient forhydrolysis. At 0° C., several days is usually necessary. The FormulaXXIX PGE-type product is isolated by conventional means.

Referring to Chart E, there is shown the transformation of lactol XXV to4,5-didehydro-PGF₁α and 4,5-didehydro-PGE₁ -type compounds. In Chart E,"m", R₂, M₁, M₂, L and R₇ have the same meanings as above.

The Formula XXV lactol is transformed to acid XXX, for example, byreaction with silver oxide. Tetrahydrofuran is a suitable diluent forthis reaction mixture. Reaction temperatures of from 10° to 100° C. maybe employed. The reaction ordinarily is completed within a few hours.

The Formula XXX acid is trnasformed to the Formula XXXI lactone byreaction with pyridine hydrochloride. Dichloromethane is a suitablesolvent for this reaction. Reaction temperatures of 15° to 40° C. may beemployed. The reaction ordinarily is completed within a few hours. Thereaction is carried out with exclusion of atmospheric moisture, forexample, under a nitrogen atmosphere.

The Formula XXXI lactone is transformed to the 4,5-didehydro-PGF₁αcompounds XXXV and to the 4,5-didehydro-PGE₁ compounds XXXIV by stepscorresponding to those employed for transforming lactone XI to FormulaXVI PGE₂ compound and Formula XVII PGF₂ compound, as described for ChartA.

Referring to Chart F, there is shown the transformation of the FormulaXIX compound to 4,5-didehydro-11-deoxy-15-methyl ether-PGF₁α and4,5-didehydro-11-deoxy-15-methyl ether-PGE₁ -type compounds. In Chart F,"m", R₂, M₃, L, R₇ and R₁₅ have the same meanings as above. ##STR60##The procedures of Chart D are followed, except that the Formula XIXcompound is used as the starting material, instead of the Formula XIIIcompound of Chart D. Under these conditions, it is not required to forma silylated intermediate, such as the Formula XXVI compound of chart D.Rather, in Chart F, the Formula XXXVIII PGF-type compound can bedirectly oxidized to form the Formula XXXIX PGE-type product.

Referring to Chart G, there is shown the transformation of the FormulaXXVI compound to 4,5-didehydro-11-deoxy-15-methyl-PGF₁α compounds. InChart G, "m", R₂, A, M₁, L and R₇ have the same meanings as above.

In the first step of Chart G, the Formula XXVI compounds are oxidized tothe intermediate Formula LX 15-oxo acids. For this purpose, reagentssuch as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, activated manganesedioxide, or nickel peroxide are used, according to procedures known inthe art. See Fieser et al., "Reagents for Organic Synthesis," John Wileyand Sons, Inc., New York, N.Y., (1967) pp. 215, 637, and 731.

The Formula XL 15-oxo compounds are transformed to silyl derivatives ofFormula XLI by procedures known in the art. See, for example, Pierce,"Silylation of Organic Compounds," Pierce Chemical Co., Rockford, Ill.(1968). The 9-hydroxy group of the Formula XL reactants are therebytransformed to --O--Si(A)₃ moieties wherein A is as defined above, andsufficient of the silylating agent is used for that purpose according toknown procedures. The --COOH moiety thereby defined is simultaneouslytransformed to --COO--Si(A)₃, additonal silylating agent being used forthis purpose. This latter transformation is aided by excess silylatingagent and prolonged treatment. ##STR61## The necessary silylating agentfor these transformations are known in the art or are prepared bymethods known in the art. See, for example, Post, "Silicones and OtherOrganic Silicon Compounds," Reinhold Publishing Corp., New York, N.Y.(1949).

The Formula XLI compound is transformed to the final 15-methylsubstituted compounds of Formulas XLII and XLIII by first reacting thesilyl compound with a Grignard reagent of the formula CH₃ MgHal, whereinHal is chloro, bromo, or iodo. For this purpose, it is preferred thatHal be bromo. This reaction is carried out by the usual procedure forGrignard reactions, using diethyl ether as a reaction solvent andsaturated aqueous ammonium chloride solution to hydrolyze the Grignardcomplex. The resulting disilyl compound is then hydrolyzed with water toremove the silyl groups. For this purpose, it is advantageous to use amixture of water and sufficient of a water-miscible solvent, e.g.,ethanol to give a homogenous reaction mixture. The hydrolysis is usuallycomplete in 2 to 6 hours at 25° C., and is preferably carried out in anatmosphere of an inert gas, e.g., nitrogen or argon.

The mixture of 15-α and 15-α isomers obtained by this Grignard reactionand hydrolysis is separated by procedures known in the art forseparating mixtures of prostanoic acid derivatives, for example, bychromatography on neutral silica gel. In some instances, the lower alkylesters, especially the methyl esters of a pair of 15-α and 15-β isomersare more readily separated by silica gel chromatography than are thecorresponding acids. In those cases, it is advantageous to esterify themixture of acids as described below, separate the two esters, and then,if desired, saponify the esters by procedures known in the art forsaponification of prostaglandins F.

The 4,5-didehydro-11-deoxy-15-methyl-PGE-type compounds are preparedfrom the above-15-substituted PGF-type compounds of Formulas XLII andXLIII following the steps of Chart H. In Chart H, "m", R₂, R₁₆, L and R₇have the same meanings as above. M₇ is ##STR62## wherein A has the samemeaning as above.

Following the final three steps of Chart D, using the same reagents andconditions, the Formula LIV compound is transformed to the PGE-typecompounds represented by Formula XLVI.

Chart I shows the transformation of the Formula XLVII PGE-type compoundsto the corresponding PGF-type compounds. In Chart I, R₁, R₂, R₇, M, L,X, Y and m are as defined above.

The various PGF.sub.α -type and PGF.sub.β -type compounds encompassed byFormula XLVIII are prepared by carbonyl reduction of the correspondingPGE-type compounds. For example, carbonyl reduction of11-deoxy-2,2-difluoro-15-methyl-PGE₂ gives a mixture of11-deoxy-2,2-difluoro-15-methyl-PGF₂α and11-deoxy-2,2-difluoro-15-methyl-PGF₂β.

These ring carbonyl reductions are carried out by methods known in theart for ring carbonyl reductions of known prostanoic acid derivatives.See, for example, Bergstrom et al, Arkiv Kemi 19, 563 (1963), Acta Chem.Scand. 16, 969 (1962), and British Specification No. 1 097 533. Anyreducing agent is used which does not react with carbon-carbon doublebonds or ester groups. Preferred reagents are lithium (tri-tertbutoxy)aluminum hydroxide, the metal borohydrides, e.g., sodium, potassium andzinc borohydrides and metal trialkoxy borohydrides, e.g., sodiumtrimethoxyborohydride. The mixtures of alpha and beta hydroxy reductionproducts are separated into the individual alpha and beta isomers bymethods known in the art for the separation of analogous pairs of knownisomeric prostanoic acid derivatives. See, for example, Bergstrom etal., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965), andGreen et al., J. Lipid Research 5, 117 (1964). Alternatively used arepartition chromatographic procedures, both normal, reversed phase,preparative thin layer and column chromatography, and countercurrentdistribution procedures. ##STR63##

The 13,14-dihydro-PG-type compounds of Formula VIII, wherein Y is --CH₂CH₂ -- and X is cis --CH═CH--CH₂ --, or cis --CH₂ --CH═CH--, areprepared by reducing the Formula XI compound of Charts A and B, theFormula XXI compound of Chart C, the Formula XXV compound of Chart D, orthe Formula XXXVII compound of Chart F, to the corresponding13,14-dihydro compound according to the process steps of Chart J. Therespective thus-obtained 13,14-dihydro compounds of Formulas XLIX to LIIare then transformed to the 13,14-dihydro-PG-type compounds by theremaining steps of Charts A-G, respectively. In Chart J, M₁, M₃, M₄, Land R₇ are as defined above.

Reducing agents useful for effecting the transformations shown in ChartJ are known in the art. Thus, hydrogen is used at atmospheric pressureor low pressure with catalysts such as palladium on charcoal or platinumoxide. The respective Formulas XLIX to LII compounds are separated fromtheir starting materials or other compounds by methods known in the art,e.g. silica gel chromatography.

Reference to Chart K will make clear the formation of the13,14-dihydro-PG₁ -type compounds of Formula VIII, wherein Y is --CH₂CH₂ -- and X is --(CH₂)₃ --. In Chart K, R₁, R₂, R₇, E, M, L, X and mare as defined above. ##STR64##

The various 13,14-dihydro-PG₁ -type compounds are prepared bycarbon-carbon double bond reduction of the corresponding PGE, PGF.sub.α,and PGF.sub.β type compounds containing a trans double bond at 13,14. Acis double bond can also be present in the carboxy-terminated side chainof the unsaturated reactant, and will be reduced at the same time to--CH₂ CH₂ --.

These reductions are carried out by reacting the unsaturated PGE, or PGFtype compound with diimide, following the general procedure described byvan Tamelen et al., J. Am. Chem. Soc, 83, 3726 (1961). See also Fieseret al., "Topics in Organic Chemistry," Reinhold Publishing Corp., NewYork, pp. 432-434 (1963) and references cited therein. The unsaturatedacid of ester reactant is mixed with a salt of azodiformic acid,preferably an alkali metal salt such as the disodium or dipotassiumsalt, in the presence of an inert diluent, preferably a lower alkanolsuch as methanol of ethanol, and preferably in the absence ofsubstantial amounts of water. At least one molecular equivalent of theazodiformic acid salt is used for each multiple bond equivalent of theunsaturated reactant. The resulting suspension is then stirred,preferably with exclusion of oxygen, and the mixture is made acid,advantageously with a carboxylic acid such as acetic acid. When areactant wherein R₁ is hydrogen is used, the carboxylic acid reactantalso serves to acidify an equivalent amount of the azodiformic acidsalt. A reaction temperature in the range about 10° to about 40° C. isusually suitable. Within that temperature range, the reaction is usuallycomplete within less than 24 hours. The desired dihydro product is thenisolated by conventional methods, for example evaporation of thediluent, followed by separation from inorganic materials by solventextraction.

The reductions are also carried out by catalytic hydrogenation. For thatpurpose, palladium catatlyst, especially on a carbon carrier, arepreferred. It is also preferred that the hydrogenation be carried out inthe presence of an inert liquid diluent, for example, methanol, ethanol,dioxane, ethyl acetate, and the like. Hydrogenation pressures rangingfrom about atomspheric to about 50 p.s.i., and hydrogenationtemperatures ranging from about 10° to about 100° C. are preferred. Theresulting fully saturated product is isolated from the hydrogenationreaction mixture by conventional methods, for example, removal of thecatalyst by filtration or centrifugation, followed by evaporation of thesolvent.

In all of the above-described reactions, the products are separated byconventional means from the starting materials and impurities, forexample by silica gel chromatography monitored by thin-layerchromatography (TLC).

Optically active compounds are obtained from optically activeintermediates according to the process steps of Charts A-K. When racemicintermediates are used in reactions corresponding to the processes ofCharts A-K, inclusive, and racemic products are obtained, these racemicproducts may be used in their racemic form or, if preferred, they may beresolved as optically active isomers by procedures known in the art.

For example, when final compound VIII is a free acid, the dl formthereof is resolved in the d and l forms by reacting said free acid byknown general procedures with an optically active base, e.g., brucine orstrychine, to give a mixture of two diastereoisomers which are separatedby known general procedures, e.g., fractional crystallization, to givethe separate diastereoisomeric salts. The optically active acid ofFormula VIII is then obtained by treatment of the salt with an acid byknown general procedures.

Referring to Chart A, when a Formula XI compound is prepared by reactinga racemic compound corresponding to Formula IX with a racemic Wittigreagent, there are obtained two pairs of racemates which are separableinto pairs of racemic compounds by methods known in the art, e.g. silicagel chromatography. When a racemic compound corresponding to Formula IXis reacted with an optically active isomer of the Wittig reagent, thereare obtained two diastereomers corresponding to the Formula XI compoundwhich are separated by conventional methods, e.g. by silica gelchromatography.

It is preferred that the Formula IX compound by used in the opticallyactive form which will lead to an 11-deoxy prostaglandin analog of thenatural configuration. For this purpose, there is provided a process forresolving a racemic mixture of an oxo compound of the formula ##STR65##and of the mirror image thereof, which comprises the steps of

(a) converting the oxo compound by reaction with an optically activeephedrine to a mixture of oxazolidine diastereomers,

(b) separating at least one oxazolidine diastereomer from said mixture,

(c) hydrolyzing said oxazolidine to free the optically active oxocompound, and

(d) recovering said optically active oxo compound.

In carrying out the resolution of the Formula LV ketone, there isprepared an oxazolidine by reaction of the ketone with an opticallyactive ephedrine, e.g. d- or l-ephedrine or d- or l-pseudoephedrine.Approximately equimolar quantities of the reactants are employed in asolvent such as benzene, isopropyl ether, or dichloromethane. Thereaction proceeds smoothyl over a wide range in temperature, for example10° to 80° C., although for some reactants the range 20° to 30° C. ispreferred for convenience. The reaction occurs quickly, within minutes,whereupon the solvent is removed, preferably under vacuum. The productconsists of the diastereomers of the ketone-ephedrine product, i.e. theoxazolidines. At least one of the diastereomers is separated by methodsknown in the art, including crystallization and chromatography. In thisresistance, crystallization is used as the preferred method. Repeatedrecrystallization of the thus-obtained solid oxazolidine from a suitablesolvent, e.g., isopropyl ether, yields one of the diastereomers insubstantially pure form. The oxazolidine is then hydrolyzed byprocedures known in the art to release the ketone.

The mother liquor from the recrystallized diastereomer contains theoptical isomer having opposite configuration. A preferred method forisolating this second diastereomer, however, is to prepare theoxazolidine of the racemic ketone using ephedrine of the oppositeconfiguration to that first employed above, and thereafterrecrystallizing as above. Finally, hydrolysis and recovery yield theresolved Formula LV ketone in opposite configuration to that firstobtained above.

Each optically active ketone can be converted to an aldehyde of theformula ##STR66## or the mirror image thereof, using the procedures ofCorey et al., Tetrahedron Lett. 49, 4753 (1971). That ketone isespecially useful which yields the Formula IX aldehyde which producesthe 11-deoxy prostaglandin analogs having the natural configuration.

Likewise, the above process of resolution applied to the racematecontaining the Formula IX aldehyde yields the optically active FormulaIX aldehyde which produces the 11-deoxy prostaglandin analogss havingthe natural configuration.

As discussed above, the processes of Charts A-K, inclusive, leadvariously to acids (R₁ is hydrogen) or to esters (R₁ is alkyl,cycloalkyl, aralkyl, phenyl or substituted phenyl, as defined above).When an acid has been prepared and an alkyl, cycloalkyl or aralkyl esteris desired, esterification is advantageously accomplished by interactionof the acid with the appropriate diazohydrocarbon. For example, whendiazomethane is used, the methyl esters are produced. Similar use ofdiazoethane, diazobutane, 1-diazo-2 ethylhexane, diazodecane,diazocyclohexane and phenyldiazomethane, for example, gives the ethyl,butyl, 2-ethylhexyl, decyl and cyclohexyl and benzyl esters,respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with diazohydrocarbon be no longerthan necessary to effect the desired esterification, preferably aboutone to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons, are known in the art or can be prepared by methodsknown in the art. See, for example, Organic Reactions, John Wiley andSons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carbonyl moiety of theacid compounds comprises transformation of the free acid to thecorresponding metal salt, followed by interaction of that salt with analkyl iodide. Examples of suitable iodides are methyl iodide, ethyliodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyliodide, cyclopentyl iodide, benzyl iodide, phenethyl and the like. Themetal salts are prepared by conventional methods, for example, bydissolving the acid in cold dilute aqueous ammonia, evaporating theexcess ammonia at reduced pressure, and then adding the stoichiometricamount of silver nitrate.

The phenyl and substituted phenyl esters of the acid compounds areprepared by silylating the acid to protect the hydroxy groups, forexample, replacing each --OH with --O--Si-- (CH₃)₃. Doing that may alsochange --COOH to --COO--SI--(CH₃)₃. A brief treatment of the silylatedcompound with water will change --COO--Si--(CH₃)₃ back to --COOH.Procedures for this silylation are known in the art and are discussedhereinabove. Then, treatment of the silylated compound with oxalylchloride gives the acid chloride which is reacted with phenol or theappropriate substituted phenol to give a silylated phenyl or substitutedphenyl ester. Then the silyl groups, e.g., --O--Si--(CH₃)₃ are changedback to --OH by treatment with dilute acetic acid. Procedures for thesetransformations are known in the art.

When the processes of Charts A-K, inclusive, yield an ester, such aswhere R₁ is methyl, the free acid products are obtained by methods knownin the art. For example, the PG compounds are subjected to enzymatichydrolysis using an esterase enzyme composition obtained by acetoneextraction at low temperature from the marine invertebrate Plexaurahomomalla (Esper), 1972. Plexaura homomalla is a member of the subclassOctocorallia, order Goroacea, suborder Holazonia, family Plexauridae,genus plexaura. See, for example, Bayer, "The Shallow-Water Octocoralliaof the West Indian Region", Martinus Nyhoff, The Hague (1961). Asolution of PG ester in ethanol or benzene is contacted with a mixtureof the esterase enzyme composition and water and is stirred until theester is hydrolyzed, generally about 18 -24 hours at 25° C. See forreference E. G. Daniels, Producing an Esterase, U.S. Pat. No. 3,761,356.Alternatively, direct saponification is used.

The final Formula VIII compounds prepared by the processes of thisinvention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed above. These transformations are carriedout by a variety of procedures known in the art to be generally usefulfor the preparation of inorganic, i.e., metal or ammonium, salts, amineacid additional salts, and quaternary ammonium salts. The choice ofprocedure depends in part upon the solubility characteristics of theparticular salt to be prepared. In the case of the inorganic salts, itis usually suitable to dissolve the Formula VIII acid in watercontaining the stoichiometric amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. For example,such use of sodium hydroxide, sodium carbonate, or sodium bicarbonategives a solution of the sodium salt. Evaporation of the water oraddition of a water-miscible solvent of moderate polarity, for example,a lower alkanol or a lower alkanone, gives the solid inorganic salt ifthat form is desired.

To produce an amine salt, the Formula VIII acid is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the latterare diethyl ether and benzene. At least a stoichiometric amount of aminecorresponding to the desired cation is then added to that solution. Ifthe resulting salt does not precipitate, it is usually obtained in solidform by addition of a miscible diluent of low polarity or byevaporation. If the amine is relatively volatile, any excess can easilybe removed by evaporation. It is preferred to use stoichiometric amountsof the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe Formula VIII acid with the stoichiometric amount of thecorresponding quaternary ammonium hydroxide in water, solution, followedby evaporation of the water.

The final Formula VIII acids or esters prepared by the processes of thisinvention, wherein R₆ is hydrogen, are transformed to lower alkanoatesby interaction of the Formula VIII hydroxy compound with acarboxyacylating agent, preferably the anhydride of a lower alkanoicacid, i.e., an alkanoic acid of two to 8 carbon atoms, inclusive. Forexample, use of acetic anhydride gives the corresponding acetate.Similar use of propionic anhydride, isobutyric anhydride, and hexanoicacid anhydride gives the corresponding carboxyacylates.

The carboxyacylation is advantageously carried out by mixing the hydroxycompound and the acid anhydride, preferably in the presence of atertiary amine such as pyridine or triethylamine. A substantial excessof the anhydride is used, preferably about 10 to about 1000 moles ofanhydride per mole of the hydroxy compound reactant. The excessanhydride serves as a reaction diluent and solvent. An inert organicdiluent, for example, dioxane, can also be added. It is preferred to useenough of the tertiary amine to neutralize the carboxylic acid producedby the reaction, as well as any free carboxyl groups present in thehydroxy compound reactant.

The carboxyacylation reaction is preferably carried out in the rangeabout 0° to about 100° C. The necessary reaction time will depend onsuch factors as the reaction temperature, and the nature of theanhydride and tertiary amine reactants. With acetic anhydride, pyridine,and a 25° C. reaction temperature, a 12 to 24-hour reaction time isused.

The carboxyacylated product is isolated from the reaction mixture byconventional methods. For example, the excess anhydride is decomposedwith water, and the resulting mixture acidified and then extracted witha solvent such as diethyl ether. the desired carboxyacylate is recoveredfrom the diethyl ether extract by evaporation. The carboxyacylate isthen purified by conventional methods, advantageously by chromatography.

By this procedure, the Formula VIII 11-deoxy PGE-type compounds aretransformed to monoalkanoates.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following preparationsand examples.

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin-Elmer model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

Mass spectra are recorded on an Atlas CH-4 mass spectrometer with a TO-4source (ionization voltage 70 ev).

NMR spectra are recorded on a Varian A-60 spectrophotometer indeuterochloroform solutions with tetramethylsilane as an internalstandard.

"Brine", herein, refers to an aqueous saturated sodium chloridesolution.

Preparation 1: 4,4-Difluoro-4-carboxybutyltriphenyl phosphonium bromide,Br(C₆ H₅)₃ P(CH₂)₃ CF₂ COOH

1. Methyl furoate (50.4 g.) dissolved in methanol (180 ml.) ishydrogenated in the presence of a 5% palladium on charcoal catalyst (1g.) at a hydrogen pressure of 50 p.s.i. Following filtration, washingand distillation there is recovered methyltetrahydrofuroate (46.7 g.)boiling at 32-35° C. under 0.1 mm. Hg.

2. To 25 g. of methyl tetrahydrofuroate obtained in step 1, there isadded a reagent obtained by bubbling anhydrous HBr through 50 ml. ofacetic anhydride until a specific gravity of 1.3 is reached. Thisaddition is made while excluding moisture and with cooling and stirring.The reaction is allowed to proceed overnight, then the reaction mixtureis placed on crushed ice and water and then extracted with diethylether, the ether extract is washed with sodium hydroxide, dried oversodium sulfate, filtered and evaporated to yield an oil which isdistilled to yield 31.6 g. of methyl-2-acetoxy-5-bromopentanoate,boiling at 93-99° C. under 0.2-0.3 mm. Hg

3. To a solution of 60 g. of the product of step 2 in 200 ml. ofmethanol, there is added 100 ml. of ice cold methanol saturated with HBrand the mixture is allowed to stand at room temperature overnight. Afterremoval of the solvent, the residue is dissolved in ethyl acetate,washed with aqueous sodium hydroxide and then brine, dried over sodiumsulfate, filtered, the solvent is evaporated, and the resultant oil isdistilled to give 28.8 g. of methyl 2-hydroxy-5-bromo-pentanoate.

4. To a solution of 34.4 g. of the product of step 3 in 400 ml. ofacetone, there is added with stirring 75 ml. of Jones reagent at a ratesuch that the reaction temperature is between 30° and 40° C. Thereaction mixture is stirred for 1.5 hours after completing adding thereagent, then 150 ml. of isopropyl alcohol is added and stirring iscontinued for 30 mins. The reaction mixture is diluted with water andextracted with methylene chloride, the extract is washed with brine,dried over sodium sulfate, filtered and evaporated to obtain 30.8 g. ofa pale yellow oil which is used in the next step without purification.Analysis of a sample of the oil showed that it comprised methyl2-oxo-5-bromo-pentanoate.

5. A solution of 30.8 g. of the product of step 4 in methylene chloride(195 ml.) is added dropwise, with stirring, into 195 ml. of FluorezeM(PCR Incorporated) under dry nitrogen atmosphere cooled in a dryice/acetone bath to provide a reaction temperature of -35° to -45° C.After stirring for one hour, the cooling bath is removed and the mixtureis diluted with methylene chloride and water, then extracted withmethylene chloride. The extracts are washed with water, aqueouspotassium hydrogen carbonate and brine, and then dried over sodiumsulfate. After filtration and evaporation of the solvent, the brown oilis distilled to recover 14 g. of methyl 2,2-difluoro-5-bromo-pentanoate,boiling at 34°-48° C. at 0.1 mm. Hg.

6. Into 175 ml. of aqueous HBr there is added 28 g. of the product ofstep 5 and the reaction mixture is stirred at room temperature for threehours. The reaction mixture is cooled in an ice bath and diluted withdiethyl ether. The aqueous layer is extracted with diethyl ether, thecombined ether solutions are washed with water, dried over sodiumsulfate, and the solvent is evaporated to yield 27.7 g. of pale yellowoil of 2,2-difluoro-5-bromo-pentanoic acid which is used in the nextstep without further purification.

7. Triphenylphosphine (156 g.) and 2,2-difluoro-5-bromo-pentanoic acid(120 g.) are heated in 125 ml. of benzene at reflux for 18 hours. Thecrystalline product is filtered off, washed with benzene andrecrystallized from methanol-diethyl ether.

Preparation 2: 6-Carboxyhexyltriphenylphosphonium bromide, Br(C₆ H₅)₃P(CH₂)₆ COOH.

Triphenylphosphine (156 g.) and 7-bromoheptanoic acid (115 g.) areheated in 125 ml. of benzene at reflux for 18 hrs. The crystallineproduct is filtered off, washed with benzene, and recrystallized frommethanol-diethyl ether, m.p. 185°-187° C.

Preparation 3: 2β-[(3S)-3-[(Tetrahydropyran-2-yl)oxy]trans-1-octenyl]-5α-hydroxy-1α-cyclopentaneacetaldehyde, γ-Lactol (FormulaXIII: ##STR67## and R₇ is n-butyl)

a. Refer to Chart A. The formula-IX starting material,5α-hydroxy-2β-carboxaldehyde-1α-cyclopentane-acetic acid γ lactone isfirst prepared in optically active form. A solution of the racemiccompound (E. J. Corey et al., Tetrahedron Lett. No. 49, 4753 (1971) 15.4g.) and 1-ephedrine (16.5 g.) in 150 ml. of benzene is concentratedunder reduced pressure to a residue. The residue is triturated withdiethyl ether and then dissolved in isopropyl ether. The solution ischilled to yield crystals of one of the diastereomeric oxazolidines. Theoxazolidine is hydrolyzed to the oxo compound and ephedrine by contractwith water, preferably with an acid catalyst, as is known in the art(see Elderfeld Heterocyclic Compounds, Vol. 5, page 394, Wiley, N.Y.1957). Thus, the above oxazolidine (1.3 g.) is stirred in a solution oftetrahydrofuran-water-acetic acid (25 ml.: 25 ml.: 5 ml.) for 4 hr. atabout 25° C. under nitrogen. The solvents are removed under reducedpressure and the residue is mixed with 25 ml. of water. The mixture isextracted several times with benzene, and the combined benzene layersare washed with water, dried over sodium sulfate, and concentrated underreduced pressure to yield an optically active isomer of the formula-IXcompound; called "the isomer of Preparation 3a" herein. Following theprocedure of part a above, but replacing 1-ephedrine with d-ephedrine,there is obtained another diastereomeric oxazolidine which yields onhydrolysis an enantiomer of the isomer above, called "the isomer ofPreparation 3a" herein.

b. Compound X is prepared as follows. There is first prepared a solutionof the anion of dimethyl 2-oxoheptyl phosphonate (E. J. Corey et al., J.Am. Chem. Soc. 90, 3247 (1968)). The phosphonate (8.0 g.) is added inportions over a 2-3 min. period to a stirred mixture of sodium hydride(1.75 g. of 50%) in 250 ml. of dry tetrahydrofuran under nitrogenpreviously cooled to 5° C. Stirring is continued at about 25° C. for atleast one hr. and the mixture is cooled to 0° C. There is then added abenzene solution of the formula IX aldehyde and stirring is continuedfor 1.5 hr. at about 25° C. Then about 3 ml. of acetic acid is addeddropwise and the mixture is concentrated under reduced pressure. Theresidue is taken up in 400 ml. of ethyl acetate, washed with water andbrine, dried over sodium sulfate, and concentrated under reducedpressure. The residue is dissolved in 50 ml. of dichloromethane andchromatographed on silica gel (500 g.) by elution gradient with 25-30%ethyl acetate in Skellysolve B. Those fractions shown by TLC to be freeof starting material are combined and concentrated to an oil of theFormula X compound.

c. To a mixture of zinc borohydride prepared from zinc chloride(anhydrous, 19 g.) and sodium borohydride (4.3 g.) in 120 ml. of dry1,2-dimethoxyethane under nitrogen stirred for 20 hr. and then cooled to-20° C., is added the Formula X ketone above (10.5 g.) in 55 ml. of1,2-dimethoxyethane. The mixture is stirred at -20° C. for 17 hr.,warmed to room temperature and stirred until reaction is complete asshown by TLC. The mixture is cooled to 0-5° C., and 30 ml. of wateradded dropwise. After hydrolysis is complete, the mixture is shaken with200 ml. of ethyl acetate and separated. The ethyl acetate layer iswashed with brine, dried over sodium sulfate, and concentrated underreduced pressure to give a mixture of the Formula XI isomers. The α andβ isomers are separated by chromatography on a silica gel column bygradient elution with 35-60% ethyl acetate in Skellysolve B. Fractionscontaining the α or β isomers, as shown by TLC, are combined andconcentrated to yield the desired hydroxy intermediates.

d. There is next prepared the Formula XII tetrahydropyranyl ether. TheFormula XI alpha hydroxy compound above (10.0 g.) is treated with 20 ml.of dihydropyran in 120 ml. of dichloromethane in the presence ofpyridine hydrochloride (0.12 g.). After about 2.5 hr. the mixture isfiltered, washed with dilute aqueous potassium bicaronate, dried andconcentrated to give the Formula XII compound wherein M₂ is ##STR68##(See Corey et al., op. cit.).

e. To a solution of above lactone XII in 250 ml. of toluene at -78° C.is added dropwise, while stirring, diisobutylaluminum hydride (12.5 ml.in 60 ml. of toluene). Stirring is continued at -78° C. for one hr.,whereupon a solution of 3 ml. of tetrahydrofuran and 1 ml. of water isadded cautiously. After the mixture is stirred an additional 0.5 hr. atabout 25° C., it is diluted with benzene and filtered. The filtrate iswashed with brine, dried, and concentrated to the Formula XIII titlecompound. See Corey et al., op. cit.

Following the procedures of steps d, and e above, but employing theFormula XI beta hydroxy compound from step c, there are obtained thecorresponding Formula XII and XIII compounds wherein M₁ is ##STR69## andM₂ is ##STR70##

Likewise following the procedures of Preparation 3, but replacing thedimethyl 2-oxoheptylphosphonate of that preparation with the variousphosphonates within the scope of ##STR71## wherein L and R₇ are asdefined above, there are obtained the corresponding Formula XIIIcompounds and their racemic compounds wherein M₂ is either ##STR72##Those phosphonates are prepared by methods described herein or known inthe art, utilizing for example the following aliphatic acid esterswithin the scope of ##STR73## wherein L and R₇ are as defined above, andR₁₈ is methyl or ethyl:

methyl butyrate

methyl 2-fluorobutyrate

ethyl 2,2-difluorobutyrate

methyl valerate

methyl 2-methylvalerate

ethyl 2-fluorovalerate

methyl hexanoate

methyl-2,2-dimethyl hexanoate

ethyl 2-methylhexanoate

methyl 2-fluorohexanoate

methyl 2,2-difluorohexanoate

methyl heptanoate

methyl 2-methylheptanoate

methyl 2-fluoroheptanoate

methyl 2,2-difluoroheptanoate

ethyl octanoate

methyl 2-fluoroctanoate

methyl 2-methyloctanoate

When the phosphonate contains an asymmetric carbon atom, e.g. when themethylene between the carbonyl and R₇ is substituted with only onemethyl or fluoro group, the phosphonate exists in either of twooptically active forms (+ or -) or their racemic (dl) mixture. Anoptically active phosphonate is obtained by starting with an appropriateoptically active isomer of the aliphatic acid. Methods of resolvingthese acids are known in the art, for example by forming salts with anoptically active base such as brucine, separating the resultingdiastereomers, and recovering the acids.

Following the procedure of Preparation 3 employing the optically activealdehyde IX of that example, each optically active phosphonate obtainedfrom the list of aliphatic acid esters above in the second paragraphfollowing Preparation 3 yields a corresponding optically active FormulaXIII γ-lactol.

Likewise following the procedure of Preparation 3, employing theoptically active aldehyde IX of that example, each racemic phosphonateobtained from the above-mentioned list of aliphatic acid esters yields apair of diastereomers, differing in their stereochemistry at the fourthcarbon of the alkyl-termiated side-chain. These diastereomers areseparated by conventinal methods, e.g. by silica gel chromatography.

Again, following the procedure of Preparation 3, employing the opticallyactive aldehyde IX of that example, each of the optically inactivephosphonates obtained from the list of aliphatic acid esters abovewherein there is no asymmetric carbon atom, i.e. R₃ and R₄ are the same,yields a corresponding optically active Formula XIII γ-lactol.

Replacing the optically active aldehyde IX with the racemic aldehyde andfollowing the procedure of Preparation 3 using each of the opticallyactive phosphonates described above, there is obtained in each case apair of diastereomers which are separated by chromatography.

Likewise following the procedure of Preparation 3, employing the racemicaldehyde with each of the racemic phosphonates described above, thereare obtained in each case two pairs of 3-oxo racemates which areseparated into pairs of racemic compounds by methods known in the art,e.g. silica gel chromatography.

Again following the procedure of Preparation 3, employing the racemicaldehyde with each of the optically inactive phosphonates describedabove, there are obtained in each case a racemic product correspondingto Formula XIII.

Preparation 4:2β-[(3S)-5-Phenyl-3-[(tetrahydropyran-2-yl)-oxy]-trans-1-pentyl]-5.alpha.-hydroxy-1α-cyclopentaneacetaldehyde,γ-Lactol (Formula XIII: M₂ is ##STR74## R₃ and R₄ are hydrogen, and R₇is ##STR75##

a. Refer to Chart A. The phosphonate anion(ylid) is first prepared asfollows. Dimethyl 2-oxo-4-phenylbutylphosphonate (prepared by methodsknown in the art from dimethyl methylphosphonate and ethyl3-phenylpropionate in the presence of butyllithium) (14.28 g.) is addedto a suspension of sodium hydride (2.7 g.) in 250 ml. of tetrahydrofuranand stirring continued for 2 hr.

To the above suspension at 0° C. is added the Formula IX aldehyde (6.0g.) in benzene. The mixture is stirred for 2 hr., acetic acid (1.5 ml.)is added, and the mixture is concentrated under reduced pressure. Theresidue is taken up in ethyl acetate, washed with brine, dried andconcentrated. Silica gel chromatography yields the Formula X compoundwherein R₇ and L are defined in the heading above.

b. To a mixture of zinc borohydride prepared from zinc chloride(anhydrous, 13.6 g.) and sodium borohydride (3.0 g.) in 120 ml. of1,2-dimethoxyethane under nitrogen stirred for 2 hr. and then cooled to-10° C., is added the Formula X ketone above (8.1 g.) in 45 ml. of1,2-dimethoxyethane. The mixture is stirred at 0° C. for 2 hr. and atabout 25° C. for 1 hr. The mixture is cooled to 0°-5° C. and 19.5 ml. ofwater is added cautiously. After hydrolysis is complete, the mixture isshaken with 200 ml. of ethyl acetate and filtered. The filtrate iswashed with brine, dried and concentrated under reduced pressure. Thealpha and beta isomers are separated by silica gel chromatography,eluting with ethyl acetate-Skellysolve B (2:1). Fractions containing theα or β isomers as shown by TLC, are combined and concentrated to yieldthe Formula XI product where M₁ is ##STR76## and the Formula XI productwherein M₁ is ##STR77##

c. There is next prepared the Formula XII tetrahydropyranyl etherwherein M₂ is ##STR78## R₃ and R₄ are hydrogen, R₇ is and R₉ is THP. TheFormula XI compound above (1.985 g.) is treated with 4.95 ml. ofdihydropyran in 45 ml. of dichloromethane in the presence ofp-toluene-sulfonic acid (0.033 g.). After about 25 min. the mixture iswashed with potassium bicarbonate solution, dried, and concentrated togive the Formula XII compound free of starting material by TLC.

d. To a solution of the above lactone in 45 ml. of toluene at -78° C. isadded dropwise, while stirring, diisobutylaluminum hydride (3.9 ml.).Stirring is continued at -78° C. for 0.5 hr., whereupon a solution of 9ml. of water in 17 ml. of tetrahydrofuran is added. After the mixture isstirred for an additional hour at about 25° C. it is filtered. Thefiltrate is washed with brine, dried, and concentrated to yield theFormula XIII title compound.

Following the procedures of steps c and d above, but employing theFormula XI β-hydroxy compound from step b, there are obtained theFormula XII and XIII compounds wherein M₁ is ##STR79## and M₂ is##STR80##

Following the procedures of Preparation 4, but replacing the Formula IXaldehyde with the racemic compound, there are obtained the racemiccomponds corresponding to Formula XIII.

Likewise, following the procedures of Preparation 4, but replacing thedimethyl 2-oxo-4-phenylbutylphosphonate of that preparation with thevarious phosphonates within the scope of ##STR81## wherein T is alkyl ofone to 3carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or--OR₈, wherein R₈ is alkyl of one to 3 carbon atoms, inclusive, and s iszero, one, 2, or 3, with the proviso that when s is 2 or 3 the T's areeither the same or different, wherein R₃ and R₄ are hydrogen, methyl orfluoro, being the same or different, with the proviso that R₃ is fluoroonly when R₄ is hydrogen or fluoro, there are obtained the correspondingFormula XIII optically active γ-lactols and their racemic compoundswherein M₂ is either ##STR82## Those phosphonates are prepared bymethods described herein or known in the art, utilizing the example thefollowing aliphatic acid esters within the scope of ##STR83## whereinR₃, R₄, s, and T are as defined above, and R₁₈ is methyl or ethyl, forexample:

methyl 3-phenylpropionate

ethyl 3-(p-chlorophenyl)propionate

methyl 3-(o,p-dichlorophenyl)propionate

methyl 2-fluoro-3-(p-tolyl)propionate

methyl 3-(m-chlorophenyl)propionate

ethyl 3-(α,α,α-trifluoro-p-tolyl)propionate

ethyl 3-(α,α,α-trifluoro-m-tolyl)propionate

methyl 2,2-difluoro-3-phenylpropionate

methyl 3-(p-fluorophenyl)propionate

methyl 3-(m-fluorophenyl)propionate

ethyl-2-methyl-3-(p-chlorophenyl)propionate

When the phosphonate contains an asymmetric carbon atom, e.g. when themethylene between the carbonyl and --CH₂ -- is substituted with only onemethyl group, the phosphonate exists in either of two optically activeforms (+ or -) or their racemic (dl) mixture. An optically activephosphonate is obtained by starting with an appropriate optically activeisomer of the aliphatic acid. Methods of resolving these acids are knownin the art, for example by forming salts with an optically active basesuch as brucine, separating the resulting diastereomers, and recoveringthe acids.

Following the procedure of Preparation 4, employing the optically activealdehyde IX of that example, each optically active phosphonate obtainedfrom the list of aliphatic acid esters above in the third paragraphfollowing Preparation 4 yields a corresponding optically active FormulaXIII γ-lactol.

Likewise following the procedure of Preparation 4, employing theoptically active aldehyde IX of that example, each racemic phosphonateobtained from the above-mentioned list of aliphatic acid esters yields apair of diastereomers, differing in their stereochemistry at the fourthcarbon of the phenoxy-terminated side-chain. These diastereomers areseparated by conventional methods, e.g. by silica gel chromatography.

Again following the procedure of Preparation 4, employing the opticallyactive aldehyde IX of that example, each of the optically inactivephosphonates obtained from the list of aliphatic acid esters abovewherein there is no asymmetric carbon atom, i.e. R₃ and R₄ are the same,yields a corresponding optically active Formula XIII γ-lactol.

Replacing the optically active aldehyde IX with the racemic aldehyde,and following the procedure of Preparation 4 using each of the opticallyactive phosphonates described above, there is obtained in each case apair of diastereomers which are separated by chromatography.

Likewise following the procedure of Preparation 4, employing the racemicaldehyde with each of the racemic phosphonates described above, thereare obtained in case two pairs of 3-oxo racemates which are separatedinto pairs of racemic compounds by methods known in the art, e.g. silicagel chromatography.

Again following the procedure of Preparation 4, employing the racemicaldehyde with each of the optically inactive phosphonates describedabove, there are obtained in each case a racemic product correspondingto Formula XIII.

Preparation 5:2β-[(3S)-4-Phenoxy-3-[(tetrahydropyran-2-yl)-oxy]-trans-1-butyl]-5α-hydroxy-1α-cyclopentaneacetaldehyde, γ-Lactol (Formula XIII: M₂ is##STR84## R₃ and R₄ are hydrogen, and R₇ is ##STR85##

a. Refer to Chart A. There is first prepared dimethyl3-phenoxyacetonylphosphonate. A solution of dimethyl methylphosphonate(75 g.) in 700 ml. of tetrahydrofuran is cooled to -75° C. undernitrogen and n-butyllithium (400 ml. of 1.6 molar solution of hexane) isadded, keeping the temperature below -55° C. The mixture is stirred for10 min. and to it is slowly added phenoxyacetyl chloride (44 g.), againkeeping the temperature below -55° C. The reaction mixture is stirred at-75° C. for 2 hr., then at about 25° C. for 16 hr. The mixture isacidifed with acetic acid and concentrated under reduced pressure. Theresidue is partitioned between diethyl ether and water, and the organicphase is dried and concentrated to the above-named intermediate, 82 g.Further treatment by silica gel chromatography yields an analyticalsample having NMR peaks at 7.4-6.7 (multiplet), 4.78 (singlet), 4.8 and4.6 (two singlets), and 3.4-3.04 (doublet)δ.

b. The phosphonate anion (ylid) is then prepared as follows. Dimethyl3-phenoxyacetonylphosphonate (step a, 9.3 g.) is added in portions to acold (5° C.) mixture of sodium hydride (1.75 g.) 50%; in 250 ml oftetrahydrofuran, and the resulting mixture is stirred for 1.5 hr. atabout 25° C.

c. To the mixture of step b is added the cold solution of the Formula IXaldehyde, and the resulting mixture is stirred about 1.6 hr. Then 3 ml.of acetic acid is added and the mixture is concentrated under reducedpressure. A solution is prepared from the residue in 500 ml. of ethylacetate, washed with several portions of water and brine, andconcentrated under reduced pressure. The residue is subjected to silicagel chromatography, eluting with ethyl acetate-Skellysolve B (isomerichexanes) (3:1). Those fractions shown by TLC to be free of startingmaterial and impurities are combined and concentrated to yield theFormula X compound.

d. Sodium borohydride (1.05 g.) is added in portions to a cold (0° C.)mixture of zinc chloride (4.4 g.) and 35 ml. of 1,2-dimethoxyethaneunder nitrogen. Stirring is continued at about 25° C. for 20 hr. Thenthe mixture is cooled to -20° C. and the Formula X 3-oxo compound (stepc, 2.6 g. in 10 ml. of 1,2-dimethoxyethane is added. The mixture isstirred at -20° C. for 6 hr., and at 25° C. for 30min. The mixture isagain cooled to -20° C. and 5 ml. of water is added dropwise. Themixture is shaken with 100 ml. of brine and ethyl acetate and theorganic layer is dried and concentrated under reduced pressure. Theresidue is chromatographed on silica gel, eluting with ethylacetate-Skellysolve B (isomeric hexanes) (3:1). Those fractions shown byTLC to be free of starting material and impurities are combined andconcentrated to yield the 3α-hydroxy Formula XI compound. Otherfractions yield the more polar 3β-hydroxy Formula XI compound.

e. The Formula XI compound from part d above is converted to the FormulaXII tetrahydropyranyl ether by reaction with 0.8 ml. of dihydropyran in10 ml. of dichloromethane in the presence of pyridine hydrochloride(about 0.03 g.). In about 2.5 hr. the mixture is filtered andconcentrated to the Formula XII product.

f. The Formula XIII title compound is prepared as follows.Diisobutylaluminum hydride (4.8 ml. of a 10% solution in toluene) isadded dropwise to a stirred solution of the Formula XIItetrahydropyranyl ether from step e above in 8 ml. of toluene cooled to-78° C. Stirring is continued at -78° C. for 0.5 hr., whereupon asolution of 3 ml. of tetrahydrofuran and 1 ml. of water is addedcautiously. After the mixture warms to 25° C. it is filtered and thefiltrate washed with brine, dried, and concentrated to the mixed alphaand beta hydroxy isomers of the Formula XIII title compounds.

Following the procedures of Preparation 5 steps e and f, but using theFormula XI 3β-hydroxy-4-phenoxy isomer of step d, there is obtained thecorresponding 3β-hydroxy Formula XIII compound, i.e. wherein M₂ is##STR86##

Following the procedure of Preparation 5, but replacing the opticallyactive Formula IX aldehyde with the racemic aldehyde, there is obtainedthe racemic 3-hydroxy-4-phenoxy-1-butenyl compound corresponding toFormula XIII.

Following the procedure of Preparation 5, but replacing thephenoxyacetyl chloride in step a with each of the aliphatic acid estersor acid chlorides within the scope of ##STR87## wherein R₃ and R₄ arehydrogen or methyl atoms, being the same or different, wherein R₁₈ ismethyl or ethyl and wherein T is alkyl of one to 3 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₈, wherein R₈ ishydrogen or alkyl of one to 3 carbon atoms, inclusive, and s is zero,one, 2 or 3, with the proviso that not more than two T's are other thanalkyl and when s is 2 or 3 the T's are either the same or different, forexample:

methyl phenoxyacetate

methyl p-fluorophenoxyacetate

methyl m-fluorophenoxyacetate

methyl 2-phenoxypropionate

methyl 2-methyl-2-phenoxypropionate

ethyl p-chlorophenoxyacetate

ethyl m-chlorophenoxyacetate

methyl (p-tolyloxy)acetate

methyl 2-(p-fluorophenoxy)propionate

ethyl (o,p-dichlorophenoxy)acetate

ethyl (α,α,α-trifluoro-p-tolyloxy)acetate

ethyl (α,α,α-trifluoro-m-tolyloxy-acetate

there are obtained the corresponding phosphonate and, thence, theFormula XIII γ-lactol.

Preparation 6:2β-[(3S)-3-Methoxy-trans-1-octenyl]-5α-hydroxy-1α-cyclopentaneacetaldehyde,γ-Lactol (Formula XIX: ##STR88## and R₇ is n-butyl)

Refer to Chart B. A mixture of the Formula XI alpha hydroxy compoundwherein M₁ is ##STR89## and R₇ is n-butyl (2.0 g.), silver oxide (4.0g.) and 50 ml of methyl iodide is stirred and heated at reflux for 68hr. The mixture is cooled and filtered, and the filtrate concentrated toa residue 2.0 g. The residue is subjected to silica gel chromatographyto yield the Formula XVIII compound.

Thereafter following the procedures of Preparation 3 step e there isobtained the Formula XIX title compound γ-lactol.

Following the procedures of Preparation 6, but replacing the Formula XIalpha hydroxy compound wherein R₇ is n-butyl with corresponding FormulaXI alpha hydroxy compounds wherein R₇ is as defined above for FormulaVIII, prepared by using the alternative phosphonate reagents describedin Preparations 3, 4 and 5, there are obtained the corresponding FormulaXIX compounds.

Preparation 7:2β-[(3S)-3-[(Tetrahydropyran-2-yl)oxy]-3-methyl-trans-1-octenyl]-5.alpha.-hydroxy-1α-cyclopentaneacetaldehyde,γ-Lactol (Formula XXIII: ##STR90## and R₇ is n-butyl).

Refer to Chart C. A solution of the Formula X oxo compound (Preparation3-step b, 0.2 g.) in 15 ml of tetrahydrofuran is treated, with stirringat -78° C., with 3M methyl magnesium bromide in ether, added dropwise.After 2 hr. there is added dropwise to the mixture at -78° C. 10 ml ofsaturated aqueous ammonium chloride. The mixture is warmed to 25° C. anddiluted with diethyl ether and water. The organic phase is washed withbrine, dried and concentrated to the mixed 15R and 15S Formula XXIcompounds.

Thereafter, following the procedures of Preparation 3 steps c-e andemploying the alpha-hydroxy compound, there are obtained the FormulaXXII compound and finally the Formula XXIII title compound.

Following the procedures of Preparation 7, but replacing the Formula Xoxo compound wherein R₇ is n-butyl with corresponding Formula X oxocompounds wherein R₇ is as defined above for Formula VIII, prepared byusing the alternative phosphonate reagents described in Preparations 3,4 and 5, there are obtained the corresponding Formula XXIII compounds.

Preparation 8:5α-Hydroxy-2β-[(3S)-3-hydroxy-trans-1-octenyl)]-1α-cyclopentanepropionaldehydeδ-Lactol (Formula XXV: ##STR91## and R₇ is n-butyl).

1. Refer to Chart D. A suspension of methoxymethyltriphenylphosphoniumchloride (Levine, J. Am. Chem. Soc. 80, 6150 (1958), 32.4 g.) in 150 mlof tetrahydrofuran (THF) is cooled to -15° C. and to it is added 69.4 mlof butyllithium (1.6 M in hexane) in 45 ml of THF. After 30 min. thereis added a solution of the Formula XIII compound (Preparation 3, 10.0g.) in 90 ml of THF. The mixture is stirred for 1.5 hrs., meanwhilewarming to about 25° C., and is then concentrated under reducedpressure. The residue is partitioned between dichloromethane and water,and the organic phase is dried and concentrated. This residue is thensubjected to chromatography over silica gel, eluting withcyclohexane-ethyl acetate (2:1). Those fractions shown by thin-layerchromatography (TLC) to contain the Formula XXIV intermediate arecombined and concentrated to yield that enol-ether, 5.2 g.

2. The above enol-ether, in 20 ml of THF, is hydrolyzed with 50 ml of66% acetic acid at about 57° C. for 2.5 hrs. The mixture is concentratedunder reduced pressure. Toluene is added to the residue and the solutionis again concentrated. Finally the residue is subjected tochromatography on silica gel, eluting with chloroform-methanol (6:1).The title compound is obtained by combining and concentrating suitablefractions, 2.54 g.: recrystallized from ethyl acetate.

Following the procedures of Preparation 8, but replacing the FormulaXIII compound with the corresponding 3β-hydroxy ether compound there isobtained the corresponding Formula XXV 3β-hydroxy compound. Likewise,the racemic 3α- or 3β-hydroxy ether compounds yield the correspondingracemic 3α or 3β-hydroxy δ-lactols.

Preparation 9:5α-Hydroxy-2β-[(3S)-3-methoxy-trans-1-octenyl]-1α-cyclopentanepropionaldehydeδ lactol (Formula XXXVII: ##STR92## and R₇ is n-butyl)

Refer to Chart F. Following the procedures of Preparation 8, butreplacing the Formula XIII compounds with the corresponding Formula XIXcompounds, there is obtained the corresponding Formula XXXVIIIcompounds.

Preparation 10: 5α-Hydroxy-2β-[(3S)-3-hydroxy-trans-1-octenyl]cyclopentane-1α-propionic acid, γ-lactone (Formula XXXI: ##STR93## andR₇ is n-butyl)

Refer to Chart E. Silver oxide reagent is prepared by the addition of145 ml of 2N NaOH to a stirred solution of silver nitrate (24.3 g.) in61 ml of water. To this mixture is added the Formula XXV lactol (17.4g.) in 110 ml of tetrahydrofuran. After 65 hr. a second slurry of silveroxide reagent is added. After 24 hr. the mixture is filtered, washedwith water and diethyl ether. The aqueous extract is acidified to pH 1-2with 2M NaHSO₄, extracted with diethyl ether, the extracts are combined,washed with water and brine, dried over sodium sulfate and azeotropedwith benzene to recover crude Formula XXX acid (14.9 g.).

The crude acid is dissolved in methylene chloride, 3 g. of pyridine HClis added and the resulting solution is stirred at room temperature undernitrogen. After 23 hr., the solvent is removed by evaporation at 40° C.,the residue is dissolved in methylene chloride, filtered through silicagel with washing with ethyl acetate and 75% acetone-methylene chloride.The filtrate is evaporated to yield a crude product which ischromatographed on silica gel packed in 20% acetone-methylene chloride.Those fractions shown by TLC to be free of starting material arecombined to give 6.1 g. of the title compound.

Example 1: 11 -Deoxy-2,2-difluoro-PGE₂ (Formula XVI: R₂ is fluoro, "m"is one, M₁ is ##STR94## R₃ and R₄ are hydrogen and R₇ is n-butyl).

a. A mixture of 57% sodium hydride in mineral oil (0.84 g.) anddimethylsulfoxide is stirred under nitrogen at 60-65° C. for 1.5 hoursand then cooled to 25° C. 4,4-Difluoro-4carboxybutyltriphenylphosphonium bromide (Preparation 1, 4.43 g.) isadded and the mixture is stirred at 36-40° C. for 15 minutes. TheFormula XIII lactol (Preparation 3) dissolved in dimethylsulfoxide (20ml) is added dropwise during 5 min. and is stirred for 16 hours. Benzene(50 ml) is added and the mixture is cooled in an ice bath and a solutionof potassium bisulfate (3.54 g.) in water (40 ml) is added. The mixtureis diluted with water (200 ml), extracted with benzene, the extractswashed with water, dried and concentrated to yield 3.7 g. of yellow oil.The oil is slurried with diethyl ether, filtered and concentrated toyield 1.50 g. of yellow oil. The oil is chromatographed on acid washedsilica gel eluted with 30% ethyl acetate - Skellysolve B. There isobtained the Formula XIV compound.

b. A stirred solution of the Formula XIV compound in acetone (15 ml) iscooled to -20° C. and there is added the Jones reagent (1 ml). Themixture is stirred at -20° C. for 38 minutes, then 1 ml of isopropanolis added and the mixture is stirred at -20° C. for an additional 10minutes. The mixture is diluted with water and extracted with diethylether. The extracts are washed with brine, dried and concentrated toyield an oil of the Formula XV compound.

c. A mixture of the oil from step b., tetrahydrofuran (5 ml), water (5ml) and acetic acid (10 ml) is heated at 42° C. for 3.5 hours. Afteradding water (20 ml) the mixture is frozen and freeze dried. The oilobtained is chromatographed on acid washed silica gel (20 g.), elutingwith 40% ethyl acetate - Skellysolve B to yield 120 mg. of the titlecompound.

Following the procedure of Example 1, but replacing the Formula XIIIcompound of that Example with the corresponding Formula XIII compoundsidentified in and following Preparations 3, 4 and 5, there are obtainedthe corresponding Formula XVI compounds, including their methyl esters,for example:

11-deoxy-2,2-difluoro-PGE₂, methyl ester

11-deoxy-2,2-difluoro-16,16-dimethyl-PGE₂, and its methyl ester

11-deoxy-2,2,16,16-tetrafluoro-PGE₂, and its methyl ester

11-deoxy-2,2-difluoro-17-phenyl-18,19,20-trinor-PGE₂, and its methylester

11-deoxy-2,2-difluoro-17-(p-fluorophenyl)-18,19,20-trinor-PGE₂, and itsmethyl ester

11-deoxy-2,2-difluoro-17-(m-trifluoromethyl)phenyl-18,19,20-trinor-PGE.sub.2,and its methyl ester

11-deoxy-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-PGE₂, and itsmethyl ester

11-deoxy-2,2-difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE₂,and its methyl ester

11-deoxy-2,2-difluoro-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₂,and its methyl ester

Following the procedure of Example 1, but replacing the4,4-difluoro-4-carboxybutyltriphenylphosphonium bromide with4-carboxybutyltriphenylphosphonium bromide,5,5-difluoro-5-carboxypentyltriphenylphosphonium bromide,5-carboxypentyltriphenylphosphonium bromide,6,6-difluoro-6-carboxyhexylphosphonium bromide or6-carboxyhexylphosphonium bromide, and replacing the Formula XIIIcompound of that Example with the corresponding Formula XIII compoundsof Preparations 3,4 and 5, yields the corresponding Formula XVIcompounds, including their methyl esters, for example:

11-deoxy-16,16-difluoro-PGE₂, and its methyl ester

11-deoxy-16-fluoro-PGE, and its methyl ester

11-deoxy-16,16-difluoro-17-phenyl-18,19,20-trinor-PGE₂, and its methylester

11-deoxy-16,16-difluoro-17-(p-fluorophenyl)-18,19,20-trinor-PGE₂, andits methyl ester

11-deoxy-16,16-difluoro-17-(m-trifluoromethyl)phenyl-18,19,20-trinor-PGE.sub.2,and its methyl ester

11-deoxy-16-phenoxy-17,18,19,20-tetranor-PGE₂, and its methyl ester

11-deoxy-16-methyl-16-phenoxy-17,18,19,20-tetranor-PGE₂, and its methylester

11-deoxy-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE₂, and its methylester

11-deoxy-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₂, andits methyl ester

Example 2: 11-Deoxy-2,2-difluoro-PGF₂α (Formula XVII: R₂ is fluoro, "m"is one, M₁ is ##STR95## R₃ and R₄ are hydrogen and R₇ is n-butyl)

The title compound is obtained by hydrolyzing the Formula XIVtetrahydropyranyl ether (Example 1, part a, 0.8 g.) in a mixture of 5.6ml. of THF and 18.6 ml. of 67% (aqueous) acetic acid. The mixture iswarmed to about 40°-50° C. for 2 hrs., then concentrated under 1 mm.pressure. The residue is dissolved in benzene and chromatographed oversilica gel using chloroform-methanol (4:1) for elution. Those fractionsshown by TLC to contain the desired product are combined andconcentrated to yield the Formula XVII title compound.

Following the procedures of Example 2, the other Formula XIV compoundsprepared as described in the first and second paragraphs followingExample 1 are transformed to the corresponding Formula XVII compounds.

Example 3: 11-Deoxy-15-methyl ether-PG-type compounds (Formula VIII: Mis ##STR96##

Refer to Chart B. Following the procedure of Examples 1 and 2, butreplacing the Formula XIII lactol of Example 1 with the Formula XIXlactol, there is obtained the corresponding 11-deoxy-15-methyl ethertype compound.

Following the procedures of Examples 1 and 2, but replacing thePreparation-3α-lactol with each of the appropriate Formula XIX lactolsprepared by transforming each of the Formula XI lactols identified inand following Preparations 3, 4 and 5, to the corresponding methylether-type lactols of Formula XIX, there are obtained the corresponding11-deoxy-15-methyl ether-type compounds, and their methyl esters, forexample:

11-deoxy-2,2-difluoro-15-methyl ether-PGE₂, and its methyl ester

11-deoxy-2,2-difluoro-15-methyl ether-17-phenyl-18,19,20-trinor-PGE₂,and its methyl ester

11-deoxy-2,2-difluoro-15-methylether-17-(p-fluorophenyl)-18,19,20-trinor-PGE₂, and its methyl ester

11-deoxy-2,2-difluoro-15-methylether-17-(m-trifluoromethyl)phenyl-18,19,20-trinor-PGE₂, and its methylester

11-deoxy-2,2-difluoro-15-methyl ether-16-phenoxy-17,18,19,20-tetranor-PGE₂, and its methyl ester

11-deoxy-2,2-difluoro-15-methylether-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE₂, and its methylester

11-deoxy-2,2-difluoro-15-methylether-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₂, and itsmethyl ester

11-deoxy-15-methyl ether-16-phenoxy-17,18,19,20-tetranor-PGE₂, and itsmethyl ester

11-deoxy-15-methyl ether-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE₂,and its methyl ester

11-deoxy-15-methyl ether-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₂, and its methyl ester

Example 4: 11-Deoxy-15-methyl-type compounds (Formula VIII: M is##STR97## and the corresponding 15-epi-isomer M is ##STR98##

Following the procedures of Example 1, but replacing the Formula XIIIcompound of Example 1 with the mixed 15-α and 15-β Formula XXIIIcompounds obtained above, there are obtained 11-deoxy-(15α and15β)-15-methyl-PGE₂ -type compounds, and their methyl esters, forexample:

11-deoxy-2,2-difluoro-15-methyl-PGE₂, and its methyl ester

11-deoxy-2,2-difluoro-15-methyl-17-phenyl-18,19,20-trinor-PGE₂, and itsmethyl ester

11-deoxy-2,2-difluoro-15-methyl-17-(p-fluorophenyl)-18,19,20-trinor-PGE.sub.2,and its methyl ester

11-deoxy-2,2-difluoro-15-methyl-17-(m-trifluoromethyl)-phenyl-18,19,20-trinor-PGE₂,and its methyl ester

11-deoxy-2,2-difluoro-15-methyl-16-phenoxy-17,18,19,20-tetranor-PGE₂,and its methyl ester

11-deoxy-2,2-difluoro-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE₂,and its methyl ester

11-deoxy-2,2-difluoro-15-methyl-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₂,and its methyl ester

11-deoxy-15-methyl-16-phenoxy-17,18,19,20-tetranor-PGE₂, and its methylester

11-deoxy-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE₂, andits methyl ester

11-deoxy-15-methyl-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE.sub.2,and its methyl ester

Example 5: 11-Deoxy-4,5,-cis-didehydro-PGF₁α (Formula XXVI: ##STR99##and R₇ is n-butyl).

Refer to Chart D. 3-Carboxypropyltriphenylphosphonium bromide isprepared by heating triphenylphosphine (156.8 g.) and 4-bromobutyricacid (100 g.) in 125 ml. of benzene at reflux for 18 hrs. Thecrystalline product is filtered off, washed with benzene, andrecrystallized from ethanol-acetonitrile-ether, 150 g., m.p. 247°-249°C.

The above phosphonium bromide (10.6 g.) is added to sodiomethylsulfinylcarbanide prepared from sodium hydride (2.08 g., 57%) and30 ml. of dimethyl sulfoxide, and the resulting Wittig reagent iscombined with the Formula XXV lactol of Preparation 8, in 20 ml. ofdimethyl sulfoxide. The mixture is stirred overnight, diluted with about200 ml. of benzene, and washed with potassium hydrogen sulfate solution.The two lower layers are washed with dichloromethane, and the organicphases are combined, washed with brine, dried, and concentrated underreduced pressure. The residue is subjected to chromatography overacid-washed silica gel, eluting with ethyl acetate-isomeric hexanes(3:1). Those fractions shown to contain the desired compound by TLC arecombined and concentrated to yield the title compound.

Following the procedures of Example 5, but replacing the Formula XXVlactol of that Example with the corresponding Formula XXV 3β-hydroxycompound obtained following Preparation 8, there is obtained thecorresponding Formula XXVI 11-deoxy-4,5-cis-didehydro-15β-PGF₁α product.

Following the procedures of Example 5, but replacing the Formula XXVlactol with the corresponding racemic 3α- or 3β-hydroxy lactol obtainedfollowing Preparation 8, there is obtained the correspondingdl-11-deoxy-4,5-cis-didehydro-PGF₁α ordl-11-deoxy-4,5-cis-didehydro-15β-PGF₁α product.

Likewise following the procedures of Example 5, but replacing theFormula XXV lactol with the various optically active or racemic 3α- or3β-hydroxy lactols obtained following Preparations 3, 4 and 5, forexample, wherein R₇ is within the scope defined for Formula VIII thereis obtained the corresponding optically active or racemic11-deoxy-4,5-cis-didehydro-PGF₁α or 11-deoxy-4,5-cis-didehydro-15β-PGF₁αtype product.

Example 6: 11-Deoxy-4,5-cis-didehydro-PGF₁α, Methyl Ester (Formula VIII:R₁ is methyl, R₂ is hydrogen, m is one, x is --CH₂ --CH═CH--, ##STR100##and R₇ is n-butyl).

A solution of diazomethane (about 50% excess) in diethyl ether (25 ml.)is added to a solution of 11-deoxy-4,5-cis-didehydro-PGF₁α (Example 5,50 mg.) in 25 ml. of a mixture of methanol and diethyl ether (1:1). Themixture is left standing at 25° C. for 5 min. and then is concentratedunder reduced pressure to the title compound.

Following the procedure of Example 6, each of the11-deoxy-4,5-cis-didehydro-PGF₁α type products obtained followingExample 5, including their 15 -epimers and the racemic forms, istransformed to a corresponding methyl ester.

Example 7: 11-Deoxy-4,5-cis-didehydro-PGE₁, Methyl Ester (Formula VIII:R₁ is methyl, R is hydrogen, m is one, x is --CH₂ --CH═CH--, ##STR101##and R₇ is n-butyl).

Refer to Chart D. 1. A solution of 11 deoxy-4,5-cis-didehydro-PGF₁α,methyl ester (Example 6, 480 mg.) in 20 ml. of acetone is cooled toabout -50° C. and to it is added 4 ml. of N-trimethylsilyldiethylamine.The mixture is kept under nitrogen at -50° C. for 2.5 hrs. Progress ofthe reaction is monitored by TLC. The reaction mixture is diluted withabout 200 ml. of diethyl ether. The solution is washed with about 150ml. of cold brine and cold saturated potassium bicarbonate solutions.The ether extract is concentrated to a residue containing11-deoxy-4,5-cis-didehydro-PGF₁α, 15-trimethylsilyl ether, methyl ester(Formula XXVII).

2. For the oxidation step, a solution of the above 15-trimethylsilylether in dichloromethane (4 ml.) is added to a solution of CrO₃-pyridine (prepared from 0.26 g. of CrO₃ and 0.4 ml. of pyridine in 16ml. of dichloromethane). The mixture is stirred for 5 min. at about 0°C. and 5 min. at about 25° C., then diluted with 10 ml. of ethyl acetateand filtered through silica gel. The solution, together with rinsings,is concentrated under reduced pressure to yield the Formula XXVIIIcompound.

3. The product of step 2 is hydrolyzed in 6 ml. of methanol, 1 ml. ofwater, and about 0.1 ml. of acetic acid at about 35° C. for 15 min. Thevolatiles are removed under reduced pressure and the residue ispartitioned between dichlormethane and water. The organic phase isseparated, dried over sodium sulfate, and concentrated under reducedpressure. The residue is chromatographed on silica gel, eluting withethyl acetate-Skellysolve B (isomeric hexanes) (4:1). Those fractionscontaining the title compound free of starting material and impuritiesare combined and concentrated to yield the title compound.

Following the procedures of Example 7, but replacing11-deoxy-4,5-cis-didehydro-PGF₁α, methyl ester, with11-deoxy-4,5-cis-didehydro-15β-PGF₁α obtained following Example 5, thereis obtained the 11-deoxy-4,5-cis-didehydro-15β-PGE₁ product. Similarly,the corresponding racemic PGF₁α type compounds yield the correspondingracemic PGE₁ type products.

Likewise following the procedures of Example 7, but employing thevarious optically active or racemic PGF₁α or 15β-PGF₁α type compounds,or their methyl esters, there are obtained the corresponding opticallyactive or racemic 11-deoxy-4,5-cis-didehydro-PGE₁ or11-deoxy-4,5-cis-didehydro-15β-PGE₁ type products, for example:

11-deoxy-4,5-cis-didehydro-16,16-difluoro-PGE₁, and its methyl ester

11-deoxy-4,5-cis-didehydro-2,2,16,16-tetrafluoro-PGE₁, and its methylester

11-deoxy-4,5-cis-didehydro-17-phenyl-18,19,20-trinor-PGE₁, and itsmethyl ester

11-deoxy-4,5-cis-didehydro-17-(p-fluorophenyl)-18,19,20-trinor-PGE₁, andits methyl ester

11-deoxy-4,5-cis-didehydro-17-(m-trifluoromethyl)phenyl-18,19,20-trinor-PGE₁, and its methyl ester

11-deoxy-4,5-cis-didehydro-16-phenoxy-17,18,19,20-tetranor-PGE₁, and itsmethyl ester

11-deoxy-4,5-cis-didehydro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE.sub.1,and its methyl ester

11-deoxy-4,5-cis-didehydro-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₁, and its methyl ester

11-deoxy-4,5-cis-didehydro-2,2-difluoro-PGE₁, and its methyl ester

11-deoxy-4,5-cis-didehydro-2,2-difluoro-17-phenyl-18,19,20-trinor-PGE₁,and its methyl ester

11-deoxy-4,5-cis-didehydro-2,2-difluoro-17-(p-fluorophenyl)-18,19,20-trinor-PGE₁,and its methyl ester

11-deoxy-4,5-didehydro-2,2-difluoro-17-(m-trifluoromethyl)phenyl-18,19,20-trinor-PGE₁,and its methyl ester

11-deoxy-4,5-cis-didehydro-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-PGE₁,and its methyl ester

11-deoxy-4,5-cis-didehydro-2,2-difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGE₁,and its methyl ester

11-deoxy-4,5-cis-didehydro-2,2-difluofo-16-(m-trifluoromethyl)phenoxy-17,18,19,20-tetranor-PGE₁,and its methyl ester

Example 8: 11-Deoxy-4,5-cis-didehydro-PGF₁α and --PGE₁ -type compounds

Refer to Chart E. Following the procedures of Examples 1 and 2, butreplacing the Formula XI lactone with the Formula XXXI lactone(Preparation 10), there are obtained the corresponding11-deoxy-4,5-cis-didehydro compounds.

Example 9: 11-Deoxy-4,5-cis-didehydro-15-methyl ether-PGF₁α and -PGE₁-type compounds

Refer to Chart F. Following the procedure of Example 5, but replacingthe formula XIII lactol with the Formula XIX lactol (Preparation 6),there are obtained the corresponding11-deoxy-4,5-cis-didehydro-15-methyl ether-PGF₁α compounds aretransformed to the corresponding PGE₁ compoumds by the procedure of step2 of Example 7.

Example 10: 11-Deoxy-4,5-cis-didehydro-15-methyl-PGF₁α, Methyl Ester(Formulas XLII and XLII: R₁ is methyl, R₂ is hydrogen, m is one, L is##STR102## and R₇ is n-butyl)

1. Refer to Chart G. A solution of 11-deoxy-4,5-cis-didehydro-PGF₁αmethyl ester (Example 6, about 0.5 g.) in 24 ml of dioxane is stirred at50° under nitrogen and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.37g.) is added. The mixture is stirred at 50° C. for 24 hrs., cooled toroom temperature, and filtered. The filter cake is washed withtetrahydrofuran, and the filtrate and wash are combined and concentratedunder reduced pressure. The residue is taken up in dichloromethane andwashed with brine, then dried over sodium sulfate and concentrated underreduced pressure. The residue is chromatographed on silica gel, elutingwith 2-10% ethanol in dichloromethane. Fractions shown by TLC to containthe desired product are combined and concentrated to give the Formula XL15-oxo intermediate.

2. A solution of about 0.4 g. of the above 15-oxo compound,hexamethyldisilazane (3 mil) and trimethylchlorosilane (0.5 ml) in 20 mlof tetrahydrofuran is allowed to stand at about 25° C. for 20 hours. Themixture is filtered and the filtrate is concentrated by evaporationunder reduced pressure. Xylene (10 ml) is added to the residue andremoved by evaporation under reduced pressure.

3. The residue of step 2 is dissolved in anhydrous ether and 110% of thetheoretical amount of 3 M methyl magnesium bromide in ether is added.The mixture is allowed to stand 20 min. at about 25° C. and poured into100 ml of saturated aqueous ammonium chloride. The ether layer isseparated, the aqueous layer is extracted with ether, and the etherextracts are combined and washed with brine, dried over sodium sulfate,and evaporated under reduced pressure. The residue is dissolved in 300ml of ethanol and 30 ml of water containing 3 drops of glacial aceticacid, and the mixture is stirred for 2 hrs. at about 25° C. The mixtureis concentrated under reduced pressure to an aqueous residue and theresidue is extracted with dichloromethane. The dichloromethane extractis evaporated under reduced pressure to give a residue which ischromatographed over silica gel, eluting with 5%-10% ethanol indichloromethane. Fractions shown by TLC to contain the desired productare combined and concentrated to yield the desired Formula XLIIcompound. Other fractions yield the 15-epimer corresponding to FormulaXLIII.

Example 11: 11-Deoxy-4,5-cis-didehydro-15-methyl-PGE₁ -type compounds(Formula XLVI: R₂ is hydrogen, m is one, L is ##STR103## and R₇ isn-butyl)

Refer to Chart H. Following the procedure of Example 7, the11-deoxy-4,5-cis-didehydro-15-methyl-PGF₁α -type compounds of Example 10are transformed to the corresponding PGE₁ -type compounds.

Example 12: 11-Deoxy-PGF-type compounds (Formula XLVIII)

Refer to Chart I. The Formula XLVII 11-deoxy-2,2-difluoro-PGE₂ (Example1, 0.2 g.) is treated in 6 ml of methanol at 0° C., while stirring, witha solution of 50 mg of sodium borohydride in 0.5 ml of water. Themixture is stirred at 0° C. for 10 min. and then diluted with 100 ml ofethyl acetate. The organic phase is washed with brine, dried, andconcentrated under reduced pressure. The residue is subjected to silicagel chromatography eluting with 5-20% ethanon in chloroform. The first200 ml of eluant are discarded and then 10 ml fractions are collectedyielding 11-deoxy-2,2-difluoro-PGF₂α. Other fractions yield11-deoxy-2,2-difluoro-PGF₂β.

Example 13: 11-Deoxy-13,14-dihydro-PG-type compounds

1. Refer to Chart J. A solution of Formula XI lactone prepared by stepsa-c of Preparation 3 (100 mg) in 10 ml of ethyl acetate is shaken withhydrogen at about one atmosphere pressure at 25° C. in the presence of5% palladium-on-carbon (15 mg). After approximately one equivalent ofhydrogen is absorbed in about one hour, the hydrogenation is stopped,and the catalyst is removed by filtration. The filtrate is evaporated,and the residue is chromatographed on silica gel, eluting with 50-100%ethyl acetate gradient in Skellysolve B. Those fractions shown by TLC tocontain the desired Formula XLIX product free of the starting productand impurities are recovered.

Following the procedures of steps d and e of Preparation 3 and Example1, but replacing the Formula XI lactol of Preparation 3 with the lactolof step 1 above, there is obtained11-deoxy-2,2-difluoro-13,14-dihydro-PGE₁.

Following the procedures of Example 13, but replacing the Formula XIlactone with the corresponding Formula XXI, Formila XXV and FormulaXXXVII compounds, there are obtained the corresponding Formula L,Formula LI and Formula LII compounds which can be transformed to11-deoxy-13,14-dihydro type compounds by the procedures of the precedingExamples.

Example 14: 11-Deoxy-13,14-dihydro-PG₁ -type compounds (Formula LIV)

Refer to Chart K. A suspension of disodium azodiformate (50 mg.) in 5ml. of absolute ethenol is added to a stirred solution of11-deoxy-2,2-difluoro-PGE₂ (Example 1, 50 mg.) in 10 ml. of absoluteethanol under nitrogen at 25° C. The mixture is made acid with glacialacetate acid, and then is stirred under nitrogen at 25° C. for 8 hr. Theresulting mixture is concentrated under reduced pressure, and theresidue is mixed with a mixture of diethyl ether and water (1:1). Thediethyl ether layer is separated, dried and concentrated to give11-deoxy-2,2-difluoro-13,14-dihydro-PGE₁.

We claim:
 1. A compound of the formula ##STR104## wherein Y is --CH₂ CH₂-- or trans--CH═CH₂ --; wherein m is one to 3, inclusive;wherein Z₃ isoxa or methylene; wherein R₁ is hydrogen, alkyl of one to 12 carbonatoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkylof 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one,2, or 3 chloro, or alkyl of one to 3 carbon atoms, inclusive or apharmacologically acceptable cation; wherein L₄ is ##STR105## or amixture of ##STR106## wherein R₃ and R₄ are hydrogen, methyl, or fluoro,being the same or different, with the proviso that one of R₃ and R₄ isfluoro only when the other is hydrogen or fluoro and Z₃ is methylene;wherein M₁ is ##STR107## wherein R₅ and R₆ are hydrogen or methyl, withthe proviso that R₅ is methyl only when R₆ is hydrogen, and R₆ is methylonly when R₅ is hydrogen; wherein X₂ is --(CH₂)₃ -- or cis-CH═CH--CH₂--; and wherein T is alkyl of one to 3 carbon atoms, inclusive, chloro,fluoro, trifluoromethyl, or --OR₈, wherein R₈ is alkyl of one to 3carbon atoms, inclusive, amd s is zero to 3, inclusive, the various T'sbeing the same or different.
 2. A compound according to claim 1, whereinZ₃ is oxa, s is zero or one, and T is chloro, fluoro, ortrifluoromethyl.
 3. A compound according to claim 2, wherein R₁ ishydrogen, alkyl of one to 2 carbon atoms, inclusive, or apharmacologically acceptable cation. 4.11-Deoxy-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-PGE₂, methylester, a compound according to claim 3.